Inhibitors of erk and methods of use

ABSTRACT

The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as ERK (MAPK). Also provided are methods of using such compounds or compositions, and methods of using these compositions to modulate the activities of one or more of these kinases, especially for therapeutic applications such as the treatment disorders such as cancer.

CROSS-REFERENCE

This application is a Continuation Application of U.S. application Ser.No. 15/896,929, filed Feb. 14, 2018, which is a Divisional Applicationof U.S. application Ser. No. 15/439,719, filed Feb. 22, 2017, which is aContinuation Application of U.S. application Ser. No. 15/026,581, filedMar. 31, 2016, which is a National Phase Entry of International PatentApplication PCT/US2014/059197, filed Oct. 3, 2014, which claims thebenefit of U.S. Provisional Application Ser. No. 61/886,552, filed onOct. 3, 2013, and U.S. Provisional Application Ser. No. 62/032,446 filedon Aug. 1, 2014, each of which is incorporated herein by reference inits entirety.

BACKGROUND OF THE INVENTION

ERK kinases are serine/threonine kinases that mediate intracellularsignal transduction pathways involved in tumor growth, progression andmetastasis. ERK is involved in the Ras/Raf/MEK/ERK pathway, which playsa central role in regulating cellular processes by relayingextracellular signals from ligand-bound cell surface receptor tyrosinekinases (RTKs) such as ErbB (e.g. EGFR, Her-2, etc), VEGF, PDGF, and FGFreceptor tyrosine kinases. Activation of an RTK triggers a series ofphosphorylation events, beginning with the activation of Ras, followedby recruitment and activation of Raf. Activated Raf then phosphorylatesMAP kinase kinase (MEK) 1/2, which then phosphorylates ERK 1/2. ERKphosphorylation by MEK occurs on Y204 and T202 for ERK1 and Y185 andT183 for ERK2 (Ahn et al., Methods in Enzymology 2001, 332, 417-431).Phosphorylated ERK dimerizes and translocates to and accumulates in thenucleus (Khokhlatchev et al., Cell 1998, 93, 605-615). In the nucleus,ERK is involved in several important cellular functions, including butnot limited to nuclear transport, signal transduction, DNA repair,nucleosome assembly and translocation, and mRNA processing andtranslation (Ahn et al., Molecular Cell 2000, 6, 1343-1354). ERK2phosphorylates a multitude of regulatory proteins, including the proteinkinases Rsk90 and MAPKAP2 ((Bjorbaek et al., 1995, J. Biol. Chem. 270,18848; Rouse et al., 1994, Cell 78, 1027), and transcription factorssuch as ATF2, Elk-1, c-Fos, and c-Myc (Raingeaud et al., 1996, Mol. CellBiol. 16, 1247; Chen et al., 1993, Proc. Natl. Acad. Sci. U.S.A. 90,10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162).Overall, treatment of cells with growth factors leads to the activationof ERK1 and ERK2 which results in proliferation and, in some cases,differentiation (Lewis et al., Adv. Cancer Res. 1998, 74, 49-139).

A wealth of studies have shown that genetic mutations and/oroverexpression of protein kinases in the Ras/Raf/MEK/ERK pathway lead touncontrolled cell proliferation and tumor formation in proliferativediseases such as cancer. For example, some cancers contain mutationswhich result in the continuous activation of this pathway due tocontinuous production of growth factors. Other mutations can lead todefects in the deactivation of the activated GTP-bound Ras complex,again resulting in activation of the MAP kinase pathway. Mutated,oncogenic forms of Ras are found in 50% of colon and >90% pancreaticcancers as well as many others types of cancers (Kohl et al., Science1993, 260, 1834-1837). Recently, bRaf mutations have been identified inmore than malignant melanomas (60%), thyroid cancers (greater than 40%)and colorectal cancers. These mutations in bRaf result in aconstitutively active Ras/Raf/MEK/ERK kinase cascade. Studies of primarytumor samples and cell lines have also shown constitutive oroveractivation of the Ras/Raf/MEK/ERK kinase pathway in cancers ofpancreas, colon, lung, ovary and kidney (Hoshino, R. et al., Oncogene1999, 18, 813-822). Further, ERK2 has been shown to play a role in thenegative growth control of breast cancer cells (Frey and Mulder, 1997,Cancer Res. 57, 628) and hyperexpression of ERK2 in human breast cancerhas been reported (Sivaraman et al., 1997, J Clin. Invest. 99, 1478).Activated ERK2 has also been implicated in the proliferation ofendothelin-stimulated airway smooth muscle cells, suggesting a role forthis kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol.Biol. 16, 589).

In view of the multitude of upstream (e.g. Ras, Raf) and downstream(e.g. ATF2, c-Fos, c-Myc) signaling proteins in the Raf/Ras/MEK/ERKpathway that have been implicated in a wide range of disorders,including but not limited to cancer, ERK has emerged as a prime targetfor drug development.

SUMMARY OF THE INVENTION

Thus, there exists a considerable need for ERK inhibitors,pharmaceutical compositions comprising such ERK inhibitor, and the usesof such ERK inhibitors for treatment and/or diagnosis of a variety ofdiseases. The present invention addresses this need and provides relatedadvantages as well.

In one aspect, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X₁ is C═O, C═S, SO, SO₂, or PO₂ ⁻;

Y is CR₅;

X₂ is NR₁ or CR₁R₁′ and X₃ is a bond, CR₃R₃′ or C═O; or

X₂-X₃ is R₁C═CR₃ or R₁C═N or N═CR₃ or NR₁₂—CR₁₁═CR₃;

X₄ is N, CR₄, C═O; X₅ is N or C;

X₆ is N or C;

X₇ is O, N, NR₇₂ or CR₇₁;

X₈ is O, N, NR₈₂ or CR₈₁;

X₉ is O, N, NR₂₂ or CR₂₁;

X₁₀ is O, N, NR₉₂ or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋ ₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³²,—SC(═O)NR³¹R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkyl-C₃₋₁₀aryl,-L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,—C(═S)OR³¹, —C(═O)SR³¹, -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkyl-C₃₋₁₀aryl,-L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, —S(O)₀₋₂N(R³¹)—, —C(═S)O—, —C(═O)S—, —NR³¹C(═NR³²)NR³²—,—NR³¹C(═NR³²)O—, —NR³¹C(═NR³²)S—, —OC(═O)O—, —OC(═O)NR³¹—, —OC(═O)S—,—SC(═O)S—, —P(O)OR³¹O—, —SC(═O)NR³¹—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents; or R₃′ is —OR⁶,—NR⁶R³⁴, —S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁, R₈₁ and R₉₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³²;

R₆ is hydrogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

each of R₇₂, R₈₂ and R₉₂ is independently hydrogen, —C₁₋₁₀ alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(═O)SR³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³²;

each of R³¹, R³², R³³ and R³⁴ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, or wherein R³¹together with R³² form a heterocyclic ring;

wherein ring A comprises one or more heteroatoms selected from N, O, orS;

wherein if X₇ is O or X₂-X₃ is R₁C═CR₃, ring A comprises at least twoheteroatoms selected from N, O, or S; and

wherein if X₃ is O or N, or X₂-X₃ is R₁C═N, at least one of X₇ or X₉ isnot N.

In some embodiments, the invention provides a compound of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the invention provides a compound of Formula I-B:

or a pharmaceutically acceptable salt or prodrug thereof.

In some cases, the invention provides a compound of Formula II:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, X₁ is C═O. In some embodiments, X₂ is NR₁. In someembodiments, X₅ is N and X₆ is C. In other embodiments, X₅ is C and X₆is C. In some embodiments, X₉ is CR₂₁.

In some embodiments, the invention provides a compound of Formula II-A:

or a pharmaceutically acceptable salt or prodrug thereof.

In other embodiments, the invention provides a compound of Formula II-B:

or a pharmaceutically acceptable salt or prodrug thereof.

In further embodiments, the invention provides a compound of FormulaII-C:

or a pharmaceutically acceptable salt or prodrug thereof.

In yet other embodiments, the invention provides a compound of FormulaII-D:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the invention provides a compound of Formula II-E:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the invention provides a compound of Formula II-F:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the invention provides a compound of Formula II-G:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E, II-F and II-G),Formula III (including Formula III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is selected from the group consisting of -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, and-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents; and L is bond. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl unsubstituted or substituted by oneor more independent R₁₂ substituents; and L is bond. In someembodiments, the C₁₋₁₀hetaryl of R₂₁ comprises one or more nitrogenatoms. In some embodiments, the C₁₋₁₀hetaryl of R₂₁ is selected from thegroup consisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl. In some embodiments, the C₁₋₁₀hetaryl of R₂₁ isunsubstituted. In other embodiments, the C₁₋₁₀hetaryl or R₂₁ issubstituted with one, two, or three independent R₁₂ substituents. Insome embodiments, each R₁₂ substituent is independently selected fromthe group consisting of —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; wherein each R₃₁ isindependently hydrogen or —C₁₋₁₀ alkyl. In further embodiments, each R₁₂substituent is independently selected from the group consisting -Me,-Et, -i-Pr, -n-Pr, OH, -OMe, -OEt, -OPr.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E, II-F and II-G),Formula III (including Formula III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, unsubstituted or substituted by one ormore independent R₁₀ or R₁₁ substituents. In other embodiments, R₁ is—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents. In yet other embodiments, R₁ is —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, unsubstituted or substituted by one ormore independent R₁₀ or R₁₁ substituents. In yet other embodiments, R₁is —C₁₋₁₀alkyl-C₃₋₁₀aryl or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, unsubstitutedor substituted by one or more independent R₁₀ or R₁₁ substituents. Infurther embodiments, wherein R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents. In some embodiments, R1 is R₁ is —C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents. In some embodiments, R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E, II-F and II-G),Formula III (including Formula III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₇₂ is H.

In other cases, the invention provides a compound of Formula III:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, X₁ is C═O. In some embodiments, X₂ is NR₁. In someembodiments, X₅ is N and X₆ is C. In other embodiments, X₅ is C and X₆is C. In some embodiments, X₈ is N and X₁₀ is N. In some embodiments, X₉is CR₂₁.

In further embodiments, the invention provides a compound of FormulaIII-A:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, the invention provides a compound of Formula III-B:

or a pharmaceutically acceptable salt or prodrug thereof.

In yet other cases, the invention provides a compound of Formula IV-A:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, X₁ is C═O. In some embodiments, X₂ is NR₁. In someembodiments, X₅ is N and X₆ is C. In other embodiments, X₅ is C and X₆is C. In some embodiments, X₈ is N. In some embodiments, X₉ is CR₂₁.

In some embodiments, the invention provides a compound of Formula IV-B:

or a pharmaceutically acceptable salt or prodrug thereof.

In other embodiments, the invention provides a compound of Formula IV-C:

or a pharmaceutically acceptable salt or prodrug thereof.

In yet other embodiments, the invention provides a compound of FormulaIV-D:

or a pharmaceutically acceptable salt or prodrug thereof.

In yet other cases, the invention provides a compound of Formula V-A:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments, X₁ is C═O. In some embodiments, X₂ is CR₁R₁′. Insome embodiments, X₅ is N and X₆ is C. In other embodiments, X₅ is C andX₆ is C. In some embodiments, X₈ is N. In some embodiments, X₉ is CR₂₁.

In some embodiments, the invention provides a compound of Formula IV-B:

or a pharmaceutically acceptable salt or prodrug thereof.

In other embodiments, the invention provides a compound of Formula IV-C:

or a pharmaceutically acceptable salt or prodrug thereof.

In yet other embodiments, the invention provides a compound of FormulaIV-D:

or a pharmaceutically acceptable salt or prodrug thereof.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E and II-F), FormulaIII (including Formula III-A and III-B), Formula IV (including IV-A,IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C and V-D), R₅is hydrogen.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E and II-F), FormulaIII (including Formula III-A and III-B), Formula IV (including IV-A,IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C and V-D), X₄is CR₄. In further embodiments, X₄ is CR₄ and R₄ is H. In otherembodiments, X₄ is N.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E, II-F and II-G),Formula III (including Formula III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), X₉ is CR₂₁ or NR₂₂ and R₂₁ or R₂₂ is halogen, —CN, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl,unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E, II-F and II-G),Formula III (including Formula III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), X₉ is CR₂₁ and R₂₁ is halogen or —CN. In other embodiments, X₉ isCR₂₁ and R₂₁ is -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₃₋₁₀heterocyclyl, unsubstituted or substituted by one or moreindependent R₁₂ substituents. In further embodiments, X₉ is CR₂₁ and R₂is -L-C₁₋₁₀hetaryl or -L-C₃₋₁₀heterocyclyl, unsubstituted or substitutedby one or more independent R₁₂ substituents.

In another aspect, the invention provides a method of inhibitingactivity of a protein kinase present in a cell, comprising contactingsaid cell with an effective amount of a compound, pharmaceuticallyacceptable salt, or prodrug disclosed herein. In some embodiments, theprotein kinase is ERK.

In some embodiments, the compound inhibits ERK at an IC50 value of lessthan about 1000 nM. In other embodiments, the compound inhibits ERK atan IC50 value of less than about 100 nM. In further embodiments, thecompound inhibits ERK at an IC50 value of less than about 10 nM.

In some embodiments, the contacting step takes place in vitro. In otherembodiments, the contacting step takes place in vivo.

The still yet another aspect, the invention provides a method ofameliorating a disorder comprising administering to a subject in needthereof an effective amount of a compound, pharmaceutically acceptablesalt, or prodrug of a compound of any of the preceding claims, whereinthe disorder is selected from the group consisting of cancer, bonedisorder, inflammatory disease, immune disease, nervous system disease,metabolic disease, respiratory disease, and cardiac disease.

In some embodiments, the disorder is cancer selected from the groupconsisting of breast cancer, pancreatic cancer, non-small cell lungcancer (NSCLC), thyroid cancer, seminomas, melanoma, bladder cancer,liver cancer, kidney cancer, myelodysplastic syndrome (MDS), acutemyelogenous leukemia (AML), and colorectal cancer. In furtherembodiments, the cancer is melanoma or colorectal cancer.

In some embodiments, the disorder is mediated by ERK 1 and/or ERK2.

In some embodiments, the method further comprises administering anotheranti-cancer agent.

The present invention also provides a pharmaceutical compositioncomprising the compound disclosed herein and a pharmaceuticallyacceptable excipient. In some embodiments, the compound is present in atherapeutically effective amount. In some embodiments, the compositionis formulated in an oral dosage. In some embodiments, the composition isformulated as a tablet or a capsule.

Additional aspects and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only illustrative embodiments of thepresent disclosure are shown and described. As will be realized, thepresent disclosure is capable of other and different embodiments, andits several details are capable of modifications in various obviousrespects, all without departing from the disclosure. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows the biological data from the ERK kinase inhibition, p90RSKELISA, and cellular proliferation assays for compounds provided by theinvention wherein, the following symbols are used: + (greater than 1000nM), ++ (250 nM to 1000 nM), +++ (50 nM to 250 nM), and ++++ (less than50 nM).

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” is used interchangeably. These terms refer to an approachfor obtaining beneficial or desired results including but not limited toa therapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the subject, notwithstanding that the subject may still beafflicted with the underlying disorder. For prophylactic benefit, thecompositions may be administered to a subject at risk of developing aparticular disease, or to a subject reporting one or more of thephysiological symptoms of a disease, even though a diagnosis of thisdisease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal so that both agents and/or theirmetabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions well known in the artand include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like, when the moleculecontains an acidic functionality; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate (methane sulfonate),ethane sulfonate, acetate, maleate, oxalate, phosphate, and the like. Ina compound with more than one basic moiety, more than one of the basicmoieties may be converted to the salt form, including but not limited toa bis- or tris-salt. Alternatively, a compound having more than onebasic moiety may form a salt at only one of the basic moieties.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction of a target protein, whether by inhibiting the activity orexpression of the target protein. Accordingly, the terms “antagonist”and “inhibitors” are defined in the context of the biological role ofthe target protein. While preferred antagonists herein specificallyinteract with (e.g. bind to) the target, compounds that inhibit abiological activity of the target protein by interacting with othermembers of the signal transduction pathway of which the target proteinis a member are also specifically included within this definition. Apreferred biological activity inhibited by an antagonist is associatedwith the development, growth, or spread of a tumor.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g. bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

As used herein, “agent” or “biologically active agent” refers to abiological, pharmaceutical, or chemical compound or other moiety.Non-limiting examples include a simple or complex organic or inorganicmolecule, a peptide, a protein, an oligonucleotide, an antibody, anantibody derivative, antibody fragment, a vitamin derivative, acarbohydrate, a toxin, or a chemotherapeutic compound. Various compoundscan be synthesized, for example, small molecules and oligomers (e.g.,oligopeptides and oligonucleotides), and synthetic organic compoundsbased on various core structures. In addition, various natural sourcescan provide compounds for screening, such as plant or animal extracts,and the like.

The term “isolated compound” or “isolated agent” refers to a biological,pharmaceutical, or chemical compound or other moiety that is isolated toa purity of greater than 90%.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “selective inhibition” or “selectively inhibit” refers to abiologically active agent refers to the agent's ability topreferentially reduce the target signaling activity as compared tooff-target signaling activity, via direct or indirect interaction withthe target.

“ERK1 and/or ERK2 activity” as applied to a biologically active agentrefers to the agent's ability to modulate signal transduction mediatedby ERK1 and/or ERK2. For example, modulation of ERK1 and/or ERK2activity is evidenced by alteration in signaling output from theRas/Raf/MEK/ERK pathway.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapaeuticsand veterinary applications. In some embodiments, the subject is amammal. In some embodiments, the subject is human.

“Radiation therapy” means exposing a subject, using routine methods andcompositions known to the practitioner, to radiation emitters such asalpha-particle emitting radionuclides (e.g., actinium and thoriumradionuclides), low linear energy transfer (LET) radiation emitters(i.e. beta emitters), conversion electron emitters (e.g. strontium-89and samarium-153-EDTMP, or high-energy radiation, including withoutlimitation x-rays, gamma rays, and neutrons.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14,and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987, both ofwhich are incorporated in full by reference herein. The term “prodrug”is also meant to include any covalently bonded carriers, which releasethe active compound in vivo when such prodrug is administered to amammalian subject. Prodrugs of an active compound, as described herein,may be prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of a hydroxy functional group, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject assay. In vitro assays encompass cell-based assaysin which cells alive or dead are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

Unless otherwise stated, the connections of compound name moieties areat the leftmost recited moiety. That is, the substituent name startswith a linking moiety, continues with any linking moieties, and endswith a terminal moiety. For example, “-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl” hasa terminal group —C₃₋₁₀cycloalkyl group attached to a linking—C₁₋₁₀alkyl moiety which is attached to an element L, which is itselfconnected to the chemical species bearing the substituent.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of hydrogen by deuterium ortritium, or the replacement of carbon by ¹³C- or ¹⁴C-enriched carbon arewithin the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

As used herein, the term “alkyl” is used to mean an alkyl having 1-10carbons—that is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons in a straightor branched configuration. In all embodiments of this invention, theterm “alkyl” includes both branched and straight chain alkyl groups, ora combination thereof. Alkyl groups are fully saturated, unsubstitutedor substituted, and can include di- and multivalent radicals, having thenumber of carbon atoms designated (i.e. C₁₋₁₀ means one to ten carbonsand C₂₋₁₀ means two to ten carbons). Typical alkyl groups are methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,n-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl, decyl, and thelike. An alkyl is unsubstituted or substituted.

The term “alkenyl” refers to a straight or branched hydrocarbon chainradical group consisting solely of carbon and hydrogen atoms, containingat least one double bond, and having from two to ten carbon atoms (i.e.—C₂₋₁₀alkenyl). Whenever it appears herein, a numerical range such as“C₂₋₁₀” refers to each integer in the given range; e.g., “C₂₋₁₀alkenyl”means that the alkenyl group may consist of 2 carbon atoms, 3 carbonatoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkenyl comprises two to eight carbon atoms (e.g.,—C₂₋₈alkenyl). In other embodiments, an alkenyl comprises two to fivecarbon atoms (e.g., —C₂₋₅alkenyl). The alkenyl is attached to the restof the molecule by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like. An alkenyl is unsubstituted or substituted.

The term “alkynyl” refers to a straight or branched hydrocarbon chainradical group consisting solely of carbon and hydrogen atoms, containingat least one triple bond, and having from two to ten carbon atoms (i.e.—C₂₋₁₀alkynyl). Whenever it appears herein, a numerical range such as“C₂₋₁₀” refers to each integer in the given range; e.g., “C₂₋₁₀alkynyl”means that the alkynyl group may consist of 2 carbon atoms, 3 carbonatoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms (e.g.,—C₂₋₈alkynyl). In other embodiments, an alkynyl has two to five carbonatoms (e.g., —C₂₋₅alkynyl). The alkynyl is attached to the rest of themolecule by a single bond, for example, ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like. An alkynyl is unsubstituted orsubstituted.

The term “heteroalkyl” refers to a straight or branched chain radicalgroup, consisting of at least one carbon atoms and at least oneheteroatom selected from the group consisting of O, N, P, Si and S, andwherein the nitrogen, phosphorus, and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P and S and Si may be placed at any interiorposition of the heteroalkyl group or at the position at which alkylgroup is attached to the remainder of the molecule. The alkyl portion ofthe moiety is unsubstituted or substituted. Examples include, but arenot limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the term“heteroalkylene” by itself or as part of another substituent means adivalent radical derived from heteroalkyl, as exemplified, but notlimited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino,alkylenediamino, and the like). Still further, for alkylene andheteroalkylene linking groups, no orientation of the linking group isimplied by the direction in which the formula of the linking group iswritten. For example, the formula —C(O)OR′— represents both —C(O)OR′—and —R′OC(O)—. As described above, heteroalkyl groups, as used herein,include those groups that are attached to the remainder of the moleculethrough a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR,and/or —SO₂R′. Where “heteroalkyl” is recited, followed by recitationsof specific heteroalkyl groups, such as —NR′R″ or the like, it will beunderstood that the terms heteroalkyl and —NR′R″ are not redundant ormutually exclusive. Rather, the specific heteroalkyl groups are recitedto add clarity. Thus, the term “heteroalkyl” should not be interpretedherein as excluding specific heteroalkyl groups, such as —NR′R″ or thelike.

The term “aromatic” or “aryl” refers to an aromatic radical with threeto sixteen carbon atoms (e.g., —C₃₋₁₆aromatic or —C₃₋₁₆aryl) which hasat least one ring having a conjugated pi electron system which iscarbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Whenever it appearsherein, a numerical range such as “C₃₋₁₀” refers to each integer in thegiven range; e.g., “—C₃₋₁₀aryl” means that the aryl group may consist of3 ring atoms, 4 ring atoms, etc., up to and including 10 ring atoms. Theterm includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of ring atoms) groups. Examples of aryl include,but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenyl,4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-methylphenyl,3-methyphenyl, 4-methylphenyl, 4-ethylphenyl, 2-methyl-3-methoxyphenyl,2,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,2,4,6-trichlorophenyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl,2,4-dimethoxynaphthyl, 4-(trifluoromethyl)naphthyl,2-iodo-4-methylnaphthyl, and the like. An aryl moiety is unsubstitutedor substituted.

The term “heteroaryl” or, alternatively, “heteroaromatic”, “hetaryl”,“heteroar” or “hetar” refers to an aromatic radical with one to sixteencarbon atoms (e.g., —C₁₋₁₆heteroaryl) that further includes one or morering heteroatoms selected from nitrogen, oxygen and sulfur, and whichmay be a monocyclic, bicyclic, tricyclic or tetracyclic ring system.Whenever it appears herein, a numerical range such as “C₁₋₁₀” refers toeach integer in the given range; e.g., “—C₁₋₁₀hetaryl” means that theheteroaryl group may consist of 1 carbon atoms, 2 carbon atoms, etc., upto and including 10 carbon atoms. An “N-containing heteroaromatic” or“N-containing heteroaryl” moiety refers to an aromatic group in which atleast one of the skeletal atoms of the ring is a nitrogen atom. Thepolycyclic heteroaryl group may be fused or non-fused. The heteroatom(s)in the heteroaryl radical is optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heteroaryl isattached to the rest of the molecule through any atom of the ring(s).Examples of heteroaryl include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). A heteroaryl moiety is unsubstituted or substituted.

The term “cycloalkyl” refers to a saturated or partially unsaturatedring structure with three to ten carbon atoms (i.e. —C₃₋₁₀cycloalkyl).Whenever it appears herein, a numerical range such as “C₃₋₁₀” refers toeach integer in the given range; e.g., “—C₃₋₁₀cycloalkyl” means that thecycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, etc., upto and including 10 carbon atoms. The term includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of ringatoms) groups. A cycloalkyl moiety is unsubstituted or substituted.

The term “heterocyclyl”, “hetcyclyl”, or “heterocycloalkyl” refers to a3-, 4-, 5-, or 6-membered saturated or partially unsaturated ringcontaining one, two, or three heteroatoms, preferably one or twoheteroatoms independently selected from oxygen, nitrogen and sulfur; orto a bicyclic ring system containing up to 10 atoms including at leastone heteroatom independently selected from oxygen, nitrogen, and sulfurwherein the ring containing the heteroatom is saturated. Whenever itappears herein, a numerical range such as “C₁₋₁₀” refers to each integerin the given range; e.g., “—C₁₋₁₀heterocyclyl” means that theheterocycloalkyl group may consist of 1 carbon atoms, 2 carbon atoms,etc., up to and including 10 carbon atoms. Examples of heterocyclylinclude, but are not limited to, tetrahydrofuranyl, tetrahydrofuryl,pyrrolidinyl, piperidinyl, 4-pyranyl, tetrahydropyranyl, thiolanyl,morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl, andchromanyl. A hetereocycloalkyl moiety is unsubstituted or substituted.

The term “—C₁₋₁₀alkyl-C₃₋₁₀aryl” refers to an aryl group, which contains3 to 10 carbons, attached to a linking alkyl group, branched or straightchain and containing 1 to 10 carbon atoms, such as for example,1-phenylethyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₁₋₁₀alkyl-C₁₋₁₀hetaryl” refers to a hetaryl group, whichcontains 1 to 10 carbons and at least one heteroatom, attached to alinking alkyl group, branched or straight chain and containing 1 to 10carbon atoms, such as for example, 2-pyrimidinylethyl, and the like.Either portion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl” refers to a cycloalkyl group,which contains 3 to 10 carbons, attached to a linking alkyl group,branched or straight chain and containing 1 to 10 carbon atoms such asfor example, 2-cyclopropylethyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl” refers to a heterocyclyl group,which contains 1 to 10 carbons, attached to a linking alkyl group,branched or straight chain and containing 1 to 10 carbon atoms such asfor example, 4-piperidinyleth-1-yl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₂₋₁₀alkenyl-C₃₋₁₀aryl” refers to an aryl group, whichcontains 3 to 10 carbons, attached to a linking alkenyl group, branchedor straight chain and containing 2 to 10 carbon atoms, such as forexample, 1-phenylvinyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl” refers to a hetaryl group, whichcontains 1 to 10 carbons and at least one heteroatom, attached to alinking alkenyl group, branched or straight chain and containing 2 to 10carbon atoms, such as for example, 2-pyrimidinylvinyl, and the like.Either portion of the moiety is unsubstituted or substituted.

The term “—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl” refers to a cycloalkyl group,which contains 3 to 10 carbons, attached to a linking alkenyl group,branched or straight chain and containing 2 to 10 carbon atoms such asfor example, 2-cyclopropylvinyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl” refers to a heterocyclylgroup, which contains 1 to 10 carbons, attached to a linking alkenylgroup, branched or straight chain and containing 2 to 10 carbon atomssuch as for example, 4-piperidinylethen-1-yl, and the like. Eitherportion of the moiety is unsubstituted or substituted.

The term “—C₂₋₁₀alkynyl-C₃₋₁₀aryl” refers to an aryl group, whichcontains 3 to 10 carbons, attached to a linking alkynyl group, branchedor straight chain and containing 2 to 10 carbon atoms, such as forexample, 1-phenylethynyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl” refers to a hetaryl group, whichcontains 1 to 10 carbons and at least one heteroatom, attached to alinking alkynyl group, branched or straight chain and containing 2 to 10carbon atoms, such as for example, 2-pyrimidinylethynyl, and the like.Either portion of the moiety is unsubstituted or substituted.

The term “—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl” refers to a cycloalkyl group,which contains 3 to 10 carbons, attached to a linking alkynyl group,branched or straight chain and containing 2 to 10 carbon atoms such asfor example, 2-cyclopropylethynyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl” refers to a heterocyclylgroup, which contains 1 to 10 carbons, attached to a linking alkynylgroup, branched or straight chain and containing 2 to 10 carbon atomssuch as for example, 4-piperidethyn-1-yl, and the like. Either portionof the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl” refers to an aryl group, whichcontains 3 to 10 carbons, attached to a linking heteroalkyl group,branched or straight chain and containing 1 to 10 carbon atoms and atleast one heteroatom, such as for example, 1-phenylethoxyethyl, and thelike. Either portion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl” refers to a hetaryl group,which contains 1 to 10 carbons and at least one heteroatom, attached toa linking heteroalkyl group, branched or straight chain and containing 1to 10 carbon atoms and at least 1 heteroatom, such as for example,2-pyrimidinylethoxyethyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl” refers to a cycloalkylgroup, which contains 3 to 10 carbons, attached to a linking heteroalkylgroup, branched or straight chain and containing 1 to 10 carbon atomsand at least one heteroatom, such as for example,2-cyclopropylethoxyethyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl” refers to a heterocyclylgroup, which contains 1 to 10 carbons, attached to a linking heteroalkylgroup, branched or straight chain and containing 1 to 10 carbon atomsand at least one heteroatom, such as for example,4-piperidinylethoxyeth-1-yl, and the like. Either portion of the moietyis unsubstituted or substituted.

The term “—C₁₋₁₀alkoxy-C₃₋₁₀aryl” refers to an aryl group, whichcontains 3 to 10 carbons, attached to a linking oxygen atom that isfurther connected to an alkyl group, branched or straight chain andcontaining 1 to 10 carbon atoms, such as for example, 1-phenoxyethyl,and the like. Either portion of the moiety is unsubstituted orsubstituted.

The term “—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl” refers to a hetaryl group, whichcontains 1 to 10 carbons and at least one heteroatom, attached to alinking oxygen atom that is further connected to an alkyl group,branched or straight chain and containing 1 to 10 carbon atoms, such asfor example, 2-pyrimidoxyethyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl” refers to a cycloalkyl group,which contains 3 to 10 carbons, attached to a linking oxygen atom thatis further connected to an alkyl group, branched or straight chain andcontaining 1 to 10 carbon atoms such as for example,2-cyclopropoxyethyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl” refers to a heterocyclylgroup, which contains 1 to 10 carbons, attached to a linking oxygen atomthat is further connected to an alkyl group, branched or straight chainand containing 1 to 10 carbon atoms such as for example,4-piperidoxyeth-1-yl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₃₋₁₀aryl-C₁₋₁₀alkyl” refers to an alkyl group, branched orstraight chain and containing 1 to 10 carbon atoms, attached to alinking aryl group, which contains 3 to 10 carbons, such as for example,4-ethylphenyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₃₋₁₀aryl-C₂₋₁₀alkenyl” refers to an alkenyl group, branchedor straight chain and containing 2 to 10 carbon atoms, attached to alinking aryl group, which contains 3 to 10 carbons, such as for example,4-ethenylphenyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₃₋₁₀aryl-C₂₋₁₀alkynyl” refers to an alkynyl group, branchedor straight chain and containing 2 to 10 carbon atoms, attached to alinking aryl group, which contains 3 to 10 carbons, such as for example,4-ethynylphenyl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₃₋₁₀aryl-C₁₋₁₀hetaryl” refers to a hetaryl group, whichcontains 1 to 10 carbons and at least one heteroatom, attached to alinking aryl group, which contains 3 to 10 carbons, such as for example,4-pyrimidinylphen-4-yl, and the like. Either portion of the moiety isunsubstituted or substituted.

The term “—C₃₋₁₀aryl-C₃₋₁₀cycloalkyl” refers to a cycloalkyl group,which contains 3 to 10 carbons, attached to a linking aryl group, whichcontains 3 to 10 carbons, such as for example, 4-cyclopropylphenyl, andthe like. Either portion of the moiety is unsubstituted or substituted.

The term “—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl” refers to a heterocyclyl group,which contains 1 to 10 carbons and at least one heteroatom, attached toa linking aryl group, which contains 3 to 10 carbons, such as forexample, 4-piperidinylphen-4-yl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₁₋₁₀hetaryl-C₁₋₁₀alkyl” refers to an alkyl group, branchedor straight chain and containing 1 to 10 carbon atoms, attached to alinking hetaryl group, which contains 1 to 10 carbons and at least oneheteroatom, such as for example, 4-ethylpyrimidin-2-yl, and the like.Either portion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl” refers to an alkenyl group,branched or straight chain and containing 2 to 10 carbon atoms, attachedto a linking hetaryl group, which contains 1 to 10 and at least oneheteroatom carbons, such as for example, 4-ethenylpyrimidin-2-yl, andthe like. Either portion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀hetaryl-C₂₋₁₀alkynyl” refers to an alkynyl group,branched or straight chain and containing 2 to 10 carbon atoms, attachedto a linking hetaryl group, which contains 1 to 10 and at least oneheteroatom carbons, such as for example, 4-ethynylpyrimidin-2-yl, andthe like. Either portion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀hetaryl-C₃₋₁₀aryl” refers to an aryl group, whichcontains 1 to 10 carbons, attached to a linking hetaryl group, whichcontains 1 to 10 carbons and at least one heteroatom, such as forexample, 4-phenylpyrimidin-2-yl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl” refers to a cycloalkyl group,which contains 3 to 10 carbons, attached to a linking hetaryl group,which contains 1 to 10 carbons and at least one heteroatom, such as forexample, 4-cyclopropylpyrimidin-2-yl, and the like. Either portion ofthe moiety is unsubstituted or substituted.

The term “—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl” refers to a heterocyclylgroup, which contains 1 to 10 carbons and at least one heteroatom,attached to a linking hetaryl group, which contains 1 to 10 carbons andat least one heteroatom, such as for example,4-piperidinylpyrimidin-2-yl, and the like. Either portion of the moietyis unsubstituted or substituted.

The term “—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl” refers to an alkyl group,branched or straight chain and containing 1 to 10 carbon atoms, attachedto a linking cycloalkyl group, which contains 3 to 10 carbons, such asfor example, 2-ethylcyclopentyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl” refers to an alkenyl group,branched or straight chain and containing 2 to 10 carbon atoms, attachedto a linking cycloalkyl group, which contains 3 to 10 carbons, such asfor example, 2-ethenylcyclopentyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl” refers to an alkynyl group,branched or straight chain and containing 2 to 10 carbon atoms, attachedto a linking cycloalkyl group, which contains 3 to 10 carbons, such asfor example, 2-ethynylcyclopentyl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl” refers to an aryl group, whichcontains 3 to 10 carbons, attached to a linking cycloalkyl group, whichcontains 3 to 10 carbons, such as for example, 2-phenylcyclopentyl, andthe like. Either portion of the moiety is unsubstituted or substituted.

The term “—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl” refers to a hetaryl group,which contains 1 to 10 carbons and at least one heteroatom, attached toa linking cycloalkyl group, which contains 3 to 10 carbons, such as forexample, 4-pyrimidinylcyclopent-2-yl, and the like. Either portion ofthe moiety is unsubstituted or substituted.

The term “—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl” refers to a heterocyclylgroup, which contains 1 to 10 carbons and at least one heteroatom,attached to a linking cycloalkyl group, which contains 3 to 10 carbons,such as for example, 4-piperidinylcyclopent-2-yl, and the like. Eitherportion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl” refers to an alkyl group,branched or straight chain and containing 1 to 10 carbon atoms, attachedto a linking heterocyclyl group, which contains 1 to 10 carbons and atleast one heteroatom, such as for example, 4-ethylpiperidin-2-yl, andthe like. Either portion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl” refers to an alkenyl group,branched or straight chain and containing 2 to 10 carbon atoms, attachedto a linking heterocyclyl group, which contains 1 to 10 and at least oneheteroatom carbons, such as for example, 4-ethenylpiperidin-2-yl, andthe like. Either portion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl” refers to an alkynyl group,branched or straight chain and containing 2 to 10 carbon atoms, attachedto a linking heterocyclyl group, which contains 1 to 10 and at least oneheteroatom carbons, such as for example, 4-ethynylpiperidin-2-yl, andthe like. Either portion of the moiety is unsubstituted or substituted.

The term “—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl” refers to an aryl group, whichcontains 1 to 10 carbons, attached to a linking heterocyclyl group,which contains 1 to 10 carbons and at least one heteroatom, such as forexample, 4-phenylpiperidin-2-yl, and the like. Either portion of themoiety is unsubstituted or substituted.

The term “—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl” refers to a hetaryl group,which contains 1 to 10 carbons and at least one heteroatom, attached toa linking heterocyclyl group, which contains 1 to 10 carbons and atleast one heteroatom, such as for example, 4-pyrimidinylpiperidin-2-yl,and the like. Either portion of the moiety is unsubstituted orsubstituted.

The term “—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl” refers to a cycloalkylgroup, which contains 3 to 10 carbons, attached to a linkingheterocyclyl group, which contains 1 to 10 carbons and at least oneheteroatom, such as for example, 4-cyclopropylpiperidin-2-yl, and thelike. Either portion of the moiety is unsubstituted or substituted.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl,trifluoromethyl, perfluoropropyl, 8-chlorononyl, and the like. Ahaloalkyl moiety can be further substituted or not further substituted.

The term “amine” or “amino” refers to a —NR′R″ moiety, where each R′ isindependently hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl, —C₁₋₁₀haloalkyl,—C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroaryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, unless statedotherwise specifically in the specification. When both R′ and R″ of a—NR′R″ moiety are not hydrogen, R′ and R″ can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. Unless stated otherwise specifically in thespecification, an amino group is optionally substituted by one or moresubstituent which independently is: —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, halo, —OH, —CN, —CF₃, —OCF₃, —NO₂, —SiMe₃,—OR′, —SR′, —OC(O)—R′, —N(R′)₂, —C(O)R′, —C(O)OR′, —OC(O)N(R′)₂,—C(O)N(R′), —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(O)N(R′)₂,—N(R′)C(NR′)N(R′)₂, —N(R′)S(O)_(t)R′ (where t is 1 or 2), —S(O)_(t)OR′(where t is 1 or 2), —S(O)_(t)N(R′)₂ (where t is 1 or 2), or PO₃(R′)₂,where each R is independently hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl,haloalkyl, —C₁₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroaryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl.

The term “amide” or “amido” refers to a chemical moiety with formula—C(O)N(R′)₂ or —NHC(O)R′, where R′ is selected from the group consistingof hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl, haloalkyl, —C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl (bonded through a ring carbon),—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl (bonded through a ring carbon), or—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl. In some embodiments, an amide is a C₁-C₄radical, which includes the amide carbonyl in the total number ofcarbons in the radical. The R′₂ of —N(R′)₂ of the amide may optionallybe taken together with the nitrogen to which it is attached to form a4-, 5-, 6-, or 7-membered ring. Unless stated otherwise specifically inthe specification, an amido group is optionally substitutedindependently by one or more of the substituents as described herein foralkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl. An amide may be anamino acid or a peptide molecule attached to a compound of Formula II orIII, thereby forming a prodrug. Any amine, hydroxy, or carboxyl sidechain on the compounds described herein can be amidified. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety.

The term “acyl” or “carbonyl” refers to the structure —C(═O)—R, in whichR is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl, haloalkyl, —C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl (bonded through a ring carbon),—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl (bonded through a ring carbon), or—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl. Unless stated otherwise specifically inthe specification, the R group of an acyl moiety is optionallysubstituted by one or more substituent which independently is:—C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, halo, —OH, —CN, —CF₃, —OCF₃,—NO₂, —SiMe₃, —OR′, —SR′, —OC(O)—R′, —N(R′)₂, —C(O)R′, —C(O)OR′,—OC(O)N(R′)₂, —C(O)N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′,—N(R′)C(O)N(R′)₂, —N(R′)C(NR′)N(R′)₂, —N(R′)S(O)_(t)R′ (where t is 1 or2), —S(O)_(t)OR′ (where t is 1 or 2), —S(O)_(t)N(R′)₂ (where t is 1 or2), or PO₃(R′)₂, where each R′ is independently hydrogen, —C₁₋₁₀alkyl,—C₁₋₁₀heteroalkyl, haloalkyl, —C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heteroaryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, or—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl.

The term “carboxyl” or “carboxy” refers to the structure —C(═O)—OR, inwhich R is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl, haloalkyl,—C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl (bonded through a ringcarbon), —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl (bonded through a ringcarbon), or —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl. Unless stated otherwisespecifically in the specification, the R group of a carboxyl moiety isoptionally substituted by one or more substituent which independentlyis: —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, halo, —OH, —CN, —CF₃, —OCF₃,—NO₂, —SiMe₃, —OR′, —SR′, —OC(O)—R′, —N(R′)₂, —C(O)R′, —C(O)OR′,—OC(O)N(R′)₂, —C(O)N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′,—N(R′)C(O)N(R′)₂, —N(R′)C(NR′)N(R′)₂, —N(R′)S(O)_(t)R′ (where t is 1 or2), —S(O)_(t)OR′ (where t is 1 or 2), —S(O)_(t)N(R′)₂ (where t is 1 or2), or PO₃(R′)₂, where each R is independently hydrogen, —C₁₋₁₀alkyl,—C₁₋₁₀heteroalkyl, haloalkyl, —C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heteroaryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, or—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl.

The term “oxo” refers to an oxygen atom that is double bonded to acarbon atom. One in the art understands that an “oxo” requires a secondbond from the atom to which the oxo is attached. Accordingly, it isunderstood that oxo cannot be substituted onto an aryl or heteroarylring, unless it forms part of the aromatic system as a tautomer.

As used herein, 0-2 in the context of —S(O)₍₀₋₂₎— are integers of 0, 1,and 2.

The term “sulfonamidyl” or “sulfonamido” refers to the structure—S(═O)₂—NR′R′, where each R′ is selected independently from the groupconsisting of hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl, —C₃₋₁₀aryl,—C₁₋₁₀heteroaryl (bonded through a ring carbon) and—C₁₋₁₀-C₁₋₁₀heterocyclyl (bonded through a ring carbon). The R′ groupsin —NR′R′ of the —S(═O)₂—NR′R′ radical may be taken together with thenitrogen to which it is attached to form a 4-, 5-, 6-, or 7-memberedring. Unless stated otherwise specifically in the specification, the R′group of a sulfonamido moiety is optionally substituted by one or moresubstituent which independently is: —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, halo, —OH, —CN, —CF₃, —OCF₃, —NO₂, —SiMe₃,—OR′, —SR′, —OC(O)—R′, —N(R′)₂, —C(O)R′, —C(O)OR′, —OC(O)N(R′)₂,—C(O)N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(O)N(R′)₂,—N(R′)C(NR)N(R′)₂, —N(R′)S(O)_(t)R′ (where t is 1 or 2), —S(O)_(t)OR′(where t is 1 or 2), —S(O)_(t)N(R′)₂ (where t is 1 or 2), or PO₃(R′)₂,where each R is independently hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heteroalkyl,haloalkyl, —C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroaryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl.

Compounds described can contain one or more asymmetric centers and maythus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The present invention includes all manner of rotamers andconformationally restricted states of a compound of the invention.

A. Generic Formulas and Detailed Description

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

A compound or a pharmaceutically acceptable or prodrug salt thereof isprovided, wherein the compound has Formula I:

X₁ is C═O, C═S, SO, SO₂, or PO₂; Y is CR₅; W is N or C;

X₂ is NR₁ or CR₁R₁′ and X₃ is null, CR₃R₃′ or C═O; or X₂-X₃ is R₁C═CR₃or R₁C═N or N═CR₃ or NR₁₂—CR₁₁═CR₃;

X₄ is N or CR₄; X₅ is N or C; X₆ is N or C; X₇ is O, N, NR₇₂ or CR₇₁; X₈is O, N, NR₈₂ or CR₈₁; X₉ is O, N, NR₂₂ or CR₂₁; X₁₀ is O, N, NR₉₂ orCR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋ ₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³²,—SC(═O)NR³¹R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkyl-C₃₋₁₀aryl,-L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³, —S(O)₀₋₂R³¹,—C(═S)OR³¹, —C(═O)SR³¹, -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkyl-C₃₋₁₀aryl,-L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, —S(O)₀₋₂N(R³¹)—, —C(═S)O—, —C(═O)S—, NR³¹C(═NR³²)NR³²—,NR³¹C(═NR³²)O—, —NR³¹C(═NR³²)S—, —OC(═O)O—, —OC(═O)NR³¹—, —OC(═O)S—,—SC(═O)S—, —P(O)OR³¹O—, —SC(═O)NR³¹—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀-hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents; or R₃′ is —OR⁶,—NR⁶R³⁴, —S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring; or R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶, —C(═O)R⁶,—C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶, wherein R⁶together with R³⁴ can optionally form a heterocyclic ring;

each of R₅, R₇₁, R₈₁ and R₉₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³'S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³²;

R₆ is hydrogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

each of R₇₂, R₈₂ and R₉₂ is independently hydrogen, —C₁₋₁₀ alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(═O)SR³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³²;

each of R³¹, R³², R³³ and R³⁴ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, orwherein R³¹ together with R³² form a heterocyclic ring;

wherein ring A comprises one or more heteroatoms selected from N, O, orS; and

wherein if X₇ is O or X₂-X₃ is R₁C═CR₃, ring A comprises at least twoheteroatoms selected from N, O, or S; and

wherein if X₂-X₃ is R₁C═N, at least one of X₇ or X₉ is not N.

In some embodiments of Formula I, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, and X₃is CR₃R₃′. In some embodiments, X₁ is C═O, X₂ is NR₁, and X₃ is C═O. Insome embodiments, X₁ is C═S, X₂ is CR₁R₁′, and X₃ is CR₃R₃′. In someembodiments, X₁ is SO₂, X₂ is NR₁, and X₃ is CR₃R₃′. In someembodiments, X₁ is SO₂, and X₂ and X₃ is R₁₁C═CR₃.

In some embodiments of Formula I, W is C, Y is CR₅, X₄ is N or CR₄, X₅is C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄, X₅is N or C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is N and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is C and X₆ is N. In some embodiments, W is N, Y is CR₅, X₄ is C═O,X₅ is C and X₆ is C. In some embodiments, W is N, Y is CR₅, X₄ is C═O,X₅ is C and X₆ is N.

In some embodiments of Formula I, X₇ is NH, X₈ is N and X₉ is CR₂₁. Insome embodiments, X₇ is N and X₈ is CR₈₁ and X₉ is CR₂₁. In someembodiments, X₇ is CR₇₁, X₈ is N and X₉ is NR₂₂. In some embodiments, X₇is CR₇₁, X₈ is N and X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is Nand X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is CR₅ and X₉ is NR₂₂.

In some embodiments of Formula I, X₁ is C═O, X₂ is NR₁, or CR₁R₁′, X₃ isCR₃R₃′ or C═O, W is N or C, Y is N or CR₅, X₄ is N, C═O or CR₄, X₅ is Nor C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂or CR₂₁. In some embodiments, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃ isCR₃R₃′, W is C, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ isNR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₂ or CR₂₁. In some embodiments, X₁is C═O, X₂ is NR₁, X₃ is CR₃R₃′, W is C, Y is CR₅, X₄ is CR₄, X₅ is C,X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉ is CR₂₁.

In some embodiments of Formula I, R₁ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkenyl-C₃₋₁₀aryl,—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkynyl-C₃₋₁₀aryl,—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀alkoxy-C₃₋₁₀aryl,—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl-C₁₋₁₀alkyl,—C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula I, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, C₃aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents.

In some embodiments of Formula I, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀alkyl-C₃₋₁₀aryl, -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋ ₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents.

In some embodiments on Formula I, R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(═O)SR³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀alkyl-C₃₋₁₀aryl, -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl,or -L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substitutedby one or more independent R₁₂ substituents. In some embodiments, R₂₂ is—OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is—OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula I, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—,—C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—,—NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, —S(O)₀₋₂N(R³¹)—, —C(═S)O—, —C(═O)S—,—NR³¹C(═NR³²)NR³²—, NR³¹C(═NR³²)O—, —NR³¹C(═NR³²)S—, —OC(═O)O—,—OC(═O)NR³¹—, —OC(═O)S—, —SC(═O)S—, —P(O)OR³¹O—, —SC(═O)NR³¹—. In someembodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—,—OC(═O)—, —C(═O)N(R³¹), —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. In some embodiments, L is a bond,—O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or—N(R³¹)C(═O)—. In some embodiments, L is a bond, —N(R³¹)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In some embodiments, L is a bond,—N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula I, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₃ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₃′ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, eachof which is unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I, R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶,—C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring. Insome embodiments, R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶together with R³⁴ can optionally form aheterocyclic ring. In some embodiments, R₃′ is —OR⁶ or —NR⁶R³⁴, whereinR⁶ together with R³⁴ can optionally form a heterocyclic ring.

In some embodiments of Formula I, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —C₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³². In someembodiments, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³².In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In someembodiments, R₅ is hydrogen.

In some embodiments of Formula I, R₆ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkenyl-C₃₋₁₀aryl,—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkynyl-C₃₋₁₀aryl,—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀alkoxy-C₃₋₁₀aryl,—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl-C₁₋₁₀alkyl,—C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents. In someembodiments, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents. In someembodiments, R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula I, each of R₇, R₈, and R₉, isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³². In some embodiments,each of R₇₁, R₈, and R₉, is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, each of R₇₁, R₈₁and R₉₁ is independently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₇₁, R₈₁ and R₉₁ is independently hydrogen,halogen, or —C₁₋₁₀alkyl. In some embodiments, each of R₇₁, R₈₁ and R₉₁is independently hydrogen.

In some embodiments of Formula I, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(═O)SR³¹. In some embodiments, each of R₇₂,R₈₂ and R₉₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, eachof R₇₂, R₈₂ and R₉₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, each of R₇₂, R₈₂ and R₉₂ is independently hydrogen or—C₁₋₁₀alkyl. In some embodiments, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen.

In some embodiments of Formula I, each of R₁₀ and R₁₄ is independently—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substitutedby one or more independent R₁₁ substituents.

In some embodiments of Formula I, each of R₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹NR³². In some embodiments, each of R₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, -C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula I, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, orwherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², R³³ and R³⁴ is independentlyhydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula I, X₁ is C═O, X₂ is NR₁ or CR₁, R₁′, X₃is CR₃R₃′ or C═O, W is C, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ isC, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₂ or CR₂₁, and X₁₀is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁, and R₈₁ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I, X₁ is C═O, X₂ is NR₁, or CR₁R₁′, X₃ isCR₃R₃′, W is C, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ isNR₇₂ or CR₇₁, X₈ is N, X₉ is NR₂₁ or CR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₁′ is hydrogen —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅ and R₇₁ is independently hydrogen, halogen, -C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′, Wis C, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ isCR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴,—C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen, halogen, or —C₁₋₁₀ alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′, Wis C, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ isCR₂₁, and X₁₀ is N;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—; or R₃′ is —OR⁶ or —NR⁶R³⁴,wherein R⁶together with R³⁴ can optionally form a heterocyclic ring;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃;

each of R³¹ and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

The invention also provides a compound as defined above, wherein thecompound is of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula I-A, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is CR₃R₃′. In some embodiments, X₁ is C═O, X₂ is NR₁, and X₃ is C═O.In some embodiments, X₁ is C═S, X₂ is CR₁R₁′, and X₃ is CR₃R₃′. In someembodiments, X₁ is SO₂, X₂ is NR₁, and X₃ is CR₃R₃′. In someembodiments, X₁ is SO₂, and X₂ and X₃ is R₁₁C═CR₃.

In some embodiments of Formula I-A, X₄ is N or CR₄, X₅ is C and X₆ is C.In some embodiments, X₄ is CR₄, X₅ is N or C and X₆ is C. In someembodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is C. In someembodiments, X₄ is CR₄, X₅ is N and X₆ is C. In some embodiments, X₄ isCR₄, X₅ is C and X₆ is N.

In some embodiments of Formula I-A, X₇ is NH, X₈ is N and X₉ is CR₂₁. Insome embodiments, X₇ is N and X₈ is CR₈₁ and X₉ is CR₂₁. In someembodiments, X₇ is CR₇₁, X₈ is N and X₉ is NR₂₂. In some embodiments, X₇is CR₇₁, X₈ is N and X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is Nand X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is C_(R) and X₉ isNR₂₂.

In some embodiments of Formula I-A, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃is CR₃R₃′ or C═O, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is N or NR₇₂or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂ or CR₂₁. In some embodiments,X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃ is CR₃R₃′, X₄ is N or CR₄, X₅ is N orC, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₂ or CR₂₁. In someembodiments, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′, X₄ is CR₄, X₅ is C, X₆is C, X₇ is NR₇₂, X₈ is N, and X₉ is CR₂₁.

In some embodiments of Formula I-A, R₁ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkenyl-C₃₋₁₀aryl,—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkynyl-C₃₋₁₀aryl,—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀alkoxy-C₃₋₁₀aryl,—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl-C₁₋₁₀alkyl,—C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula I-A, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents.

In some embodiments of Formula I-A, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀alkyl-C₃₋₁₀aryl, -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋ ₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents.

In some embodiments on Formula I-A, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(═O)SR³,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀alkyl-C₃₋₁₀aryl, -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl,or -L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substitutedby one or more independent R₁₂ substituents. In some embodiments, R₂₂ is—OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is—OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula I-A, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, —S(O)₀₋₂N(R³¹)—, —C(═S)O—,—C(═O)S—, —NR³¹C(═NR³²)NR³²—, —NR³¹C(═NR³²)O—, —NR³¹C(═NR³²)S—,—OC(═O)O—, —OC(═O)NR³¹—, —OC(═O)S—, —SC(═O)S—, —P(O)OR³¹O—,—SC(═O)NR³¹—. In some embodiments, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula I-A, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₃ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —C₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I-A, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₃′ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, eachof which is unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I-A, R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶,—C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring. Insome embodiments, R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶together with R³⁴ can optionally form aheterocyclic ring. In some embodiments, R₃′ is —OR⁶ or —NR⁶R³⁴, whereinR⁶ together with R³⁴ can optionally form a heterocyclic ring.

In some embodiments of Formula I-A, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I-A, R₅ is hydrogen, halogen,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹NR³². In some embodiments, R₅ is hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In someembodiments, R₅ is hydrogen.

In some embodiments of Formula I-A, R₆ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkenyl-C₃₋₁₀aryl,—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkynyl-C₃₋₁₀aryl,—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀alkoxy-C₃₋₁₀aryl,—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl-C₁₋₁₀alkyl,—C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents. In someembodiments, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents. In someembodiments, R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula I-A, each of R₇₁, R₈₁ and R₉₁ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³². In some embodiments,each of R₇₁, R₈₁ and R₉₁ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₇₁, R₈₁ and R₉₁ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, each of R₇₁, R₈₁ and R₉₁ isindependently hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments,each of R₇₁, R₈₁ and R₉₁ is independently hydrogen.

In some embodiments of Formula I-A, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(═O)SR³¹. In some embodiments, each of R₇₂,R₈₂ and R₉₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, eachof R₇₂, R₈₂ and R₉₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, each of R₇₂, R₈₂ and R₉₂ is independently hydrogen or—C₁₋₁₀alkyl. In some embodiments, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen.

In some embodiments of Formula I-A, each of R₁₀ and R₁₄ is independently—C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substitutedby one or more independent R₁₁ substituents.

In some embodiments of Formula I-A, each of R₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹NR³². In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₂R³¹ or —NR³¹C(═O)R³². In some embodiments,each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹. In someembodiments, each of R₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula I-A, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl,or wherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², R³³ and R³⁴ is independentlyhydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula I-A, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃is CR₃R₃′ or C═O, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ isN or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₂ or CR₂₁, and X₁₀ is N orCR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁, and R₈₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I-A, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃is CR₃R₃′, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂or CR₇₁, X₈ is N, X₉ is NR₂₁ or CR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₁′ is hydrogen —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring;

each of R₅ and R₇₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I-A, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′,Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁,and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R₃,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴,—C(═O)N(R³⁴)R⁶, or N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen, halogen, or —C₁₋₁₀ alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I-A, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′,Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁,and X₁₀ is N;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—; or R₃′ is —OR⁶ or —NR⁶R³⁴,wherein R⁶together with R³⁴ can optionally form a heterocyclic ring;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃;

each of R³¹ and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

The invention also provides a compound as defined above, wherein thecompound is of Formula I-B:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula I-B, X₂ is NR₁ or CR₁R₁′, and X₃ isCR₃R₃′. In some embodiments, X₂ is NR₁, and X₃ is C═O. In someembodiments, X₂ is CR₁R₁′, and X₃ is CR₃R₃′. In some embodiments, X₂ isNR₁, and X₃ is CR₃R₃′. In some embodiments, X₂ and X₃ is R₁₁C═CR₃.

In some embodiments of Formula I-B, W is C, Y is CR₅, X₄ is N or CR₄, X₅is C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄, X₅is N or C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is N and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is C and X₆ is N. In some embodiments, W is N, Y is CR₅, X₄ is C═O,X₅ is C and X₆ is C. In some embodiments, W is N, Y is CR₅, X₄ is C═O,X₅ is C and X₆ is N.

In some embodiments of Formula I-B, X₇ is NH, X₈ is N and X₉ is CR₂₁. Insome embodiments, X₇ is N and X₈ is CR₈₁ and X₉ is CR₂₁. In someembodiments, X₇ is CR₇₁, X₈ is N and X₉ is NR₂₂. In some embodiments, X₇is CR₇₁, X₈ is N and X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is Nand X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is CR₈ and X₉ is NR₂₂.

In some embodiments of Formula I-B, X₂ is NR₁ or CR₁R₁′, X₃ is CR₃R₃′ orC═O, W is N or C, Y is N or CR₅, X₄ is N, C═O or CR₄, X₅ is N or C, X₆is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₁, and X₉ is NR₂₂ or CR₂₁.In some embodiments, X₂ is NR₁ or CR₁R₁′, X₃ is CR₃R₃′, W is C, Y isCR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ is N,and X₉ is NR₂₂ or CR₂₁. In some embodiments, X₂ is NR₁, X₃ is CR₃R₃′, Wis C, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉is CR₂₁.

In some embodiments of Formula I-B, R₁ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkenyl-C₃₋₁₀aryl,—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkynyl-C₃₋₁₀aryl,—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀alkoxy-C₃₋₁₀aryl,—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl-C₁₋₁₀alkyl,—C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula I-B, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula I-B, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀alkyl-C₃₋₁₀aryl, -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋ ₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents.

In some embodiments on Formula I-B, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(═O)SR³,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀alkyl-C₃₋₁₀aryl, -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,-L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,-L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl,-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀aryl-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl,-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl,-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl,or -L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substitutedby one or more independent R₁₂ substituents. In some embodiments, R₂₂ is—OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is—OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula I-B, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, —S(O)₀₋₂N(R³¹)—, —C(═S)O—,—C(═O)S—, —NR³¹C(═NR³²)NR³²—, NR³¹C(═NR³²)O—, —NR³¹C(═NR³²)S—,—OC(═O)O—, —OC(═O)NR³¹—, —OC(═O)S—, —SC(═O)S—, —P(O)OR³¹O—,—SC(═O)NR³¹—. In some embodiments, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula I-B, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₃ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I-B, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₃′ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, eachof which is unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I-B, R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶,—C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring. Insome embodiments, R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶together with R³⁴ can optionally form aheterocyclic ring. In some embodiments, R₃′ is —OR⁶ or —NR⁶R³⁴, whereinR⁶ together with R³⁴ can optionally form a heterocyclic ring.

In some embodiments of Formula I-B, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³²,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹,—NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², —SC(═O)NR³¹R³²,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkenyl-C₃₋₁₀aryl, —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl,—C₂₋₁₀alkynyl-C₃₋₁₀aryl, —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀alkoxy-C₃₋₁₀aryl, —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl,—C₃₋₁₀aryl-C₁₋₁₀alkyl, —C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₃ substituents. In someembodiments, R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents. In some embodiments, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula I-B, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—SO₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³,—NR³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³,—NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³². In someembodiments, R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³².In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀ alkyl. In someembodiments, R₅ is hydrogen.

In some embodiments of Formula I-B, R₆ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkenyl-C₃₋₁₀aryl,—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, —C₂₋₁₀alkynyl-C₃₋₁₀aryl,—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl,—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, -C₁₋₁₀alkoxy-C₃₋₁₀aryl,—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, —C₃₋₁₀aryl-C₁₋₁₀alkyl,—C₃₋₁₀aryl-C₂₋₁₀alkenyl, —C₃₋₁₀aryl-C₂₋₁₀alkynyl,—C₃₋₁₀aryl-C₃₋₁₀hetaryl, —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,—C₃₋₁₀hetaryl-C₃₋₁₀aryl, —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl,—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents. In someembodiments, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents. In someembodiments, R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula I-B, each of R₇₁, R₈₁ and R₉, isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹NR³². In some embodiments, each of R₇, R₈, and R₉, isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹or —NR³¹C(═O)R³². In some embodiments, each of R₇₁, R₈, and R₉₁ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₇₁, R₈₁ and R₉₁ is independently hydrogen,halogen, or —C₁₋₁₀ alkyl. In some embodiments, each of R₇₁, R₈₁ and R₉₁is independently hydrogen.

In some embodiments of Formula I-B, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(═O)SR³¹. In some embodiments, each of R₇₂,R₈₂ and R₉₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, eachof R₇₂, R₈₂ and R₉₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, each of R₇₂, R₈₂ and R₉₂ is independently hydrogen or—C₁₋₁₀alkyl. In some embodiments, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen.

In some embodiments of Formula I-B, each of R₁₀ and R₁₄ is independently—C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substitutedby one or more independent R₁₁ substituents.

In some embodiments of Formula I-B, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³², —NR³¹C(═O)R³²,—NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³², —C(═S)OR³¹,—C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³,—OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)SR³¹, —P(O)OR³¹OR³², or—SC(═O)NR³¹NR³². In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, -C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula I-B, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl,or wherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², R³³ and R³⁴ is independentlyhydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula I-B, X₂ is NR₁ or CR₁R₁′, X₃ is CR₃R₃′ orC═O, W is C, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is N orNR₇₂ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₂ or CR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁, and R₈₁ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I-B, X₂ is NR₁, or CR₁R₁′, X₃ is CR₃R₃′,W is C, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂ orCR₇₁, X₈ is N, X₉ is NR₂₁ or CR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₁′ is hydrogen —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring;

each of R₅ and R₇₁ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀ alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I-B, X₂ is NR₁, X₃ is CR₃R₃′, W is C, Yis CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁,and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴,—C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen, halogen, or —C₁₋₁₀ alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula I-B, X₂ is NR₁, X₃ is CR₃R₃′, W is C, Yis CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁,and X₁₀ is N;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—; or R₃′ is —OR⁶ or —NR⁶R³⁴,wherein R⁶together with R³⁴ can optionally form a heterocyclic ring;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃;

each of R³¹ and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

The invention also provides a compound as defined above, wherein thecompound is of Formula II:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is CR₃R₃′. In some embodiments, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is C═O. In some embodiments, X₁ is C═S, X₂ is CR₁, and X₃ is CR₃R₃′.In some embodiments, X₁ is SO₂, X₂ is NR₁, and X₃ is CR₃R₃′. In someembodiments, X₁ is SO₂, and X₂ and X₃ is R₁₁C═CR₃.

In some embodiments of Formula II, W is C, Y is CR₅, X₄ is N or CR₄, X₅is C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄, X₅is N or C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is C and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is N and X₆ is C. In some embodiments, W is C, Y is CR₅, X₄ is CR₄,X₅ is C and X₆ is N. In some embodiments, W is N, Y is CR₅, X₄ is C═O,X₅ is C and X₆ is C. In some embodiments, W is N, Y is CR₅, X₄ is C═O,X₅ is C and X₆ is N.

In some embodiments of Formula II, X₇ is NH, X₈ is N and X₉ is CR₂₁. Insome embodiments, X₇ is N and X₈ is CR₈₁ and X₉ is CR₂₁. In someembodiments, X₇ is CR₇, X₈ is N and X₉ is NR₂₂. In some embodiments, X₇is CR₇, X₈ is N and X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is Nand X₉ is CR₂. In some embodiments, X₇ is O, X₈ is CR₁ and X₉ is NR₂₁.

In some embodiments of Formula II, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃ isCR₃R₃′ or C═O, W is N or C, Y is N or CR₅, X₄ is N, C═O or CR₄, X₅ is Nor C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂or CR₂₁. In some embodiments, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃ isCR₃R₃′, W is C, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ isNR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₂ or CR₂₁. In some embodiments, X₁is C═O, X₂ is NR₁, X₃ is CR₃R₃′, W is C, Y is CR₅, X₄ is CR₄, X₅ is C,X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉ is CR₂₁.

In some embodiments of Formula II, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁′ is hydrogen,—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula II, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments on Formula II, R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₁₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃′ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II, R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶,—C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring. Insome embodiments, R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶together with R³⁴ can optionally form aheterocyclic ring. In some embodiments, R₃′ is —OR⁶ or —NR⁶R³⁴, whereinR⁶ together with R³⁴ can optionally form a heterocyclic ring.

In some embodiments of Formula II, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula II, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula II, each of R₇₁ and R₈₁ is independentlyhydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³².In some embodiments, each of R₇₁ and R₈₁ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, each of R₇₁ and R₈₁ is independentlyhydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, each of R₇₁ andR₈₁ is independently hydrogen.

In some embodiments of Formula II, each of R₇₂ and R₈₂ is independentlyhydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or—S(O)₀₋₂R³¹. In some embodiments, each of R₇₂ and R₈₂ is independentlyhydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, each of R₇₂ and R₈₂ isindependently hydrogen or —C₁₋₁₀alkyl. In some embodiments, each of R₇₂and R₈₂ is independently hydrogen.

In some embodiments of Formula II, each of R₁₀ and R₁₄ is independently—C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substitutedby one or more independent R₁₁ substituents.

In some embodiments of Formula II, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula II, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl,or wherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², and R³³ is independently hydrogenor —C₁₋₁₀alkyl.

In some embodiments of Formula II, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃ isCR₃R₃′ or C═O, W is N or C, Y is CR₅, X₄ is N, C═O or CR₄, X₅ is N or C,X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂ orCR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁, and R₈₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula II, X₁ is C═O, X₂ is NR₁, or CR₁R₁′, X₃is CR₃R₃′, W is N or C, Y is CR₅, X₄ is N, C═O or CR₄, X₅ is N or C, X₆is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₁ or CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂, is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅ and R₇₁ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula II, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′, Wis C, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂, is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴,—C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is independently hydrogen, halogen, or —C₁₋₁₀ alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula II, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′, Wis C, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁, substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃;

each of R³¹ and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

The invention also provides a compound as defined above, wherein thecompound is of Formula II′:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II′, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is CR₃R₃′. In some embodiments, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is C═O. In some embodiments, X₁ is C═S, X₂ is CR₁, and X₃ is CR₃R₃′.In some embodiments, X₁ is SO₂, X₂ is NR₁, and X₃ is CR₃R₃′. In someembodiments, X₁ is SO₂, and X₂ and X₃ is R₁₁C═CR₃.

In some embodiments of Formula II′, Y is CR₅, X₄ is N or CR₄, X₅ is Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N or C andX₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is C.In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N and X₆ is C. In someembodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is N. In someembodiments, Y is CR₅, X₄ is C═O, X₅ is C and X₆ is C. In someembodiments, Y is CR₅, X₄ is C═O, X₅ is C and X₆ is N.

In some embodiments of Formula II′, X₇ is NH, X₈ is N and X₉ is CR₂₁. Insome embodiments, X₇ is N and X₈ is CR₈₁ and X₉ is CR₂₁. In someembodiments, X₇ is CR₇, X₈ is N and X₉ is NR₂₂. In some embodiments, X₇is CR₇, X₈ is N and X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is Nand X₉ is CR₂. In some embodiments, X₇ is O, X₈ is CR₁ and X₉ is NR₂₁.

In some embodiments of Formula II′, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃is CR₃R₃′ or C═O, Y is N or CR₅, X₄ is N, C═O or CR₄, X₅ is N or C, X₆is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂ or CR₂₁.In some embodiments, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃ is CR₃R₃′, Y isCR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ is N,and X₉ is NR₂₂ or CR₂₁. In some embodiments, X₁ is C═O, X₂ is NR₁, X₃ isCR₃R₃′, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, andX₉ is CR₂₁.

In some embodiments of Formula II′, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II′, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁′ is hydrogen,—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula II′, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments on Formula II′, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II′, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. In someembodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—,—OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In some embodiments, L is abond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In some embodiments, Lis a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II′, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II′, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃′ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II′, R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶,—C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring. Insome embodiments, R₃′ is -OR³⁴, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶together with R³⁴ can optionally form aheterocyclic ring. In some embodiments, R₃′ is —OR⁶ or —NR⁶R³⁴, whereinR⁶ together with R³⁴ can optionally form a heterocyclic ring.

In some embodiments of Formula II′, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II′, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula II′, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula II′, each of R₇₁ and R₈₁ is independentlyhydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³².In some embodiments, each of R₇₁ and R₈₁ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, each of R₇₁ and R₈₁ is independentlyhydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, each of R₇₁ andR₈₁ is independently hydrogen.

In some embodiments of Formula II′, each of R₇₂ and R₈₂ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or—S(O)₀₋₂R³¹. In some embodiments, each of R₇₂ and R₈₂ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, each of R₇₂ and R₈₂ isindependently hydrogen or —C₁₋₁₀alkyl. In some embodiments, each of R₇₂and R₈₂ is independently hydrogen.

In some embodiments of Formula II′, each of R₁₀ and R₁₄ is independently—C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substitutedby one or more independent R₁₁ substituents.

In some embodiments of Formula II′, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃.

In some embodiments of Formula II′, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl,or wherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², and R³³ is independently hydrogenor —C₁₋₁₀alkyl.

In some embodiments of Formula II′, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃is CR₃R₃′ or C═O, Y is CR₅, X₄ is N, C═O or CR₄, X₅ is N or C, X₆ is C,X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂ or CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁, and R₈₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula II′, X₁ is C═O, X₂ is NR₁, or CR₁, R′, X₃is CR₃R₃′, Y is CR₅, X₄ is N, C═O or CR₄, X₅ is N or C, X₆ is C, X₇ isNR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₁ or CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅ and R₇₁ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula II′, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′,Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉ isCR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₁₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴,—C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is independently hydrogen, halogen, or —C₁₋₁₀ alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula II′, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′,Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉ isCR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH or —CF₃;

each of R³¹ and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

The invention also provides a compound as defined above, wherein thecompound is of Formula II-A:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II-A, Y is CR₅, X₄ is N or CR₄, X₅ is Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is N or CR₄, X₅ is N or Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ isC. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N and X₆ is C. Insome embodiments, X₄ is CR₄, X₅ is C and X₆ is N.

In some embodiments of Formula II-A, X₇ is NH, X₈ is N and X₉ is CR₂₁.In some embodiments, X₇ is N and X₈ is CR₈₁ and X₉ is CR₂₁. In someembodiments, X₇ is CR₇₁, X₈ is N and X₉ is NR₂₂. In some embodiments, X₇is CR₇₁, X₈ is N and X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is Nand X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is CR₅ and X₉ is NR₂₁.

In some embodiments of Formula II-A, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is N or NR₇₁ or CR₇, X₈ is N or CR₈₁, and X₉ is NR₂ orCR₂₁. In some embodiments, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ isC, X₇ is NR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₂ or CR₂₁. In someembodiments, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N,and X₉ is CR₂₁.

In some embodiments of Formula II-A, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II-A, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments on Formula II-A, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II-A, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II-A, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II-A, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or—C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula II-A, each of R₇₁ and R₈₁ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹or —NR³¹C(═O)R³². In some embodiments, each of R₇₁ and R₁ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R or —NR³¹C(═O)R³². In some embodiments,each of R₇₁ and R₈₁ is independently hydrogen, halogen, or —C₁₋₁₀alkyl.In some embodiments, each of R₇₁ and R₈₁ is independently hydrogen.

In some embodiments of Formula II-A, each of R₇₂ and R₈₂ isindependently hydrogen, —C₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, each of R₇₂ and R₈₂ isindependently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, eachof R₇₂ and R₈₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, each of R₇₂ and R₈₂ is independently hydrogen.

In some embodiments of Formula II-A, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents. In some embodiments, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents. In some embodiments, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents.

In some embodiments of Formula II-A, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula II-A, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, orwherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², R³³ and R³⁴ is independentlyhydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-A, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂or CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which is unsubstitutedor substituted by one or more independent R₁₃ substituents;

each of R₅, R₇₁ and R₈₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²;

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ and X₉ is a heteroatom selectedfrom N, O, or S.

In some embodiments of Formula II-A, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂ orCR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,or C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents;

each of R₅, R₇₁ and R₈₁ is independently hydrogen, halogen, C₁₋₁₀ alkyl,C₃₋₁₀aryl, C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₁₀aryl, C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀ alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ and X₉ is a heteroatom selectedfrom N, O, or S.

In some embodiments of Formula II-A, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ isC, X₇ is NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl;

each of R₅, R₇₁ and R₈₇ is independently hydrogen, halogen, or —C₁₋₁₀alkyl;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹;

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀ alkyl; and

wherein at least one of X₅, X₆, X₇, X₈ and X₉ is a heteroatom selectedfrom N, O, or S.

In some embodiments of Formula II-A, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ isC, X₇ is NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl;

each of R₅, R₇₁ and R₈₁ is independently hydrogen, halogen, or—C₁₋₁₀alkyl;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independent R₁substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH or —CF₃;

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl; and

wherein at least one of X₅, X₆, X₇, X₈ and X₉ is a heteroatom selectedfrom N, O, or S.

In some embodiments of Formula II-A, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ isC, X₇ is NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, or—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is -L-C₃₋₁₀aryl or -L-C₁₋₁₀hetaryl, each of which is unsubstitutedor substituted by one or more independent R₁₂ substituents;

L is a bond or —N(R³¹)—;

R₄ is hydrogen;

each of R₅, R₇₁ and R₈₁ is independently hydrogen or —C₁₋₁₀ alkyl;

R₇₂ is hydrogen;

each of R₁₀ is independently-C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —OH, —CF₃ or—OR³¹;

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl; and

wherein at least one of X₅, X₆, X₇, X₈ and X₉ is a heteroatom selectedfrom N, O, or S.

In some embodiments of Formula II-A, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ isC, X₇ is NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is CR₂₁;

R₁ is —C₁₋₁₀alkyl or —C₁₋₁₀alkyl-C₃₋₁₀aryl, each of which isunsubstituted or substituted by one or more independent R₁₁substituents;

R₂₁ is pyridyl selected from the group consisting of 2-pyridyl,3-pyridyl and 4-pyridyl, which is unsubstituted or substituted by one ormore independent R₁₂ substituents;

L is a bond;

R₄ is hydrogen;

each of R₅, R₇₁ and R₈₁ is independently hydrogen;

R₇₂ is hydrogen;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀ alkyl, —CF₃ or—OR³¹;

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl; and

wherein at least one of X₅, X₆, X₇, X₈ and X₉ is a heteroatom selectedfrom N, O, or S.

The invention also provides a compound as defined above, wherein thecompound is of Formula II-B:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II-B, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is CR₃R₃′. In some embodiments, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is C═O. In some embodiments, X₁ is C═S, X₂ is CR₁, and X₃ is CR₃. Insome embodiments, X₁ is SO₂, X₂ is NR₁, and X₃ is CR₃R₃′. In someembodiments, X₁ is SO₂, and X₂ and X₃ is R₁C═CR₃.

In some embodiments of Formula II-B, X₁ is C═O or SO₂, X₂ is NR₁ orCR₁R₁′, X₃ is CH or C═O, Y is CR₅, and X₄ is N or CR₄. In someembodiments, X₁ is C═O or SO₂, X₂ is N_(R) or CR₁R₁′, X₃ is CH, Y is CR₅and X₄ is N or CR₄. In some embodiments, X₁ is C═O, X₂ is NR₁, X₃ is CH,Y is CR₅ and X₄ is CR₄.

In some embodiments of Formula II-B, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II-B, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁′ is hydrogen,—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula II-B, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₁₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II-B, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)⁻, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II-B, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II-B, R₃′ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃′ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II-B, R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶,—C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring. Insome embodiments, R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶together with R³⁴ can optionally form aheterocyclic ring. In some embodiments, R₃′ is —OR⁶ or —NR⁶R³⁴, whereinR⁶ together with R³⁴ can optionally form a heterocyclic ring.

In some embodiments of Formula II-B, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II-B, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula II-B, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₁₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula II-B, R₇₂ is hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is hydrogen or —C₁₋₁₀alkyl. In some embodiments, R₇₂ ishydrogen.

In some embodiments of Formula II-B, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀ alkyl, —C₁₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents. In some embodiments, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents. In some embodiments, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents.

In some embodiments of Formula II-B, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula II-B, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl,or wherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², R³³ and R³⁴ is independentlyhydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-B, X₁ is C═O or SO₂, X₂ is NR₁ orCR₁R₁′, X₃ is CR₃R₃′ or C═O, Y is CR₅ and X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, -C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;and

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula II-B, X₁ is C═O or SO₂, X₂ is NR₁ orCR₁R₁′, X₃ is CR₃R₃′, Y is CR₅ and X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl, orwherein R³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula II-B, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′,Y is CR₅ and X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴,—C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹; andeach of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-B, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′,Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R³⁴ together with R³⁴can optionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃; and

each of R³¹ and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl.

In some embodiments of Formula II-B, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′,Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, or—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is -L-C₃₋₁₀aryl or -L-C₁₋₁₀hetaryl, each of which is unsubstitutedor substituted by one or more independent R₁₂ substituents;

L is a bond or —N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, or—C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₀ is independently-C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀ alkyl, —OH, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

In some embodiments of Formula II-B, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′,Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl or —C₁₋₁₀alkyl-C₃₋₁₀aryl, each of which isunsubstituted or substituted by one or more independent R₁₁substituents;

R₂₁ is pyridyl selected from the group consisting of 2-pyridyl,3-pyridyl and 4-pyridyl, which is unsubstituted or substituted by one ormore independent R₁₂ substituents;

L is a bond;

each of R₃, R₃′ and R₄ is independently hydrogen or —C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀ alkyl, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

The invention also provides a compound as defined above, wherein thecompound is of Formula II-C:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II-C, Y is CR₅, X₄ is N or CR₄. In someembodiments of Formula II-C, Y is CR₅, X₄ is N or CR₄. In someembodiments of Formula II-C, Y is CR₅, X₄ is CR₄.

In some embodiments of Formula II-C, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II-C, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II-C, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II-C, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II-C, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula II-C, R₇₂ is hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, R₇₂ is independently hydrogen.

In some embodiments of Formula II-C, each of R₁₀ independently is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents.

In some embodiments of Formula II-C, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula II-C, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-C, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which is unsubstitutedor substituted by one or more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂ and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula II-C, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,or —C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁, substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula II-C, Y is CR₅, X₄ is CR₄;

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,or —C₂₋₁₀alkynyl;

R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-C, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH or —CF₃; and each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

In some embodiments of Formula II-C, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, or—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is -L-C₃₋₁₀aryl or -L-C₁₋₁₀hetaryl, each of which is unsubstitutedor substituted by one or more independent R₁₂ substituents;

L is a bond or —N(R³¹)—;

R₄ is hydrogen;

R₅ is hydrogen; R₇₂ is hydrogen;

each of R₁₀ is independently-C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀ alkyl, —OH, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

In some embodiments of Formula II-C, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl or —C₁₋₁₀alkyl-C₃₋₁₀aryl, each of which isunsubstituted or substituted by one or more independent R₁₁substituents;

R₂₁ is pyridyl selected from the group consisting of 2-pyridyl,3-pyridyl and 4-pyridyl, which is unsubstituted or substituted by one ormore independent R₁₂ substituents;

L is a bond;

R₄ is hydrogen;

R₅ is hydrogen; R₇₂ is hydrogen;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀ alkyl, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

The invention further provides a compound as defined above, wherein thecompound is of Formula II-D:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II-D, Y is CR₅, X₄ is N or CR₄. In someembodiments of Formula II-D, Y is CR₅, X₄ is N or CR₄. In someembodiments of Formula II-D, Y is CR₅, X₄ is CR₄.

In some embodiments of Formula II-D, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II-D, R₂, is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II-D, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. In someembodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—,—OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In some embodiments, L is abond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In some embodiments, Lis a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II-D, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II-D, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula II-D, R₇₂ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, R₇₂ is independently hydrogen.

In some embodiments of Formula II-D, each of R₁₀ independently is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents.

In some embodiments of Formula II-D, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃.

In some embodiments of Formula II-D, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-D, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,-C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which is unsubstitutedor substituted by one or more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula II-D, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,or —C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula II-D, Y is CR₅, X₄ is CR₄;

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,or —C₂₋₁₀alkynyl;

R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-D, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH or —CF₃; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

In some embodiments of Formula II-D, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, or—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is -L-C₃₋₁₀aryl or -L-C₁₋₁₀hetaryl, each of which is unsubstitutedor substituted by one or more independent R₁₂ substituents;

L is a bond or —N(R³¹)—;

R₄ is hydrogen;

R₅ is hydrogen; R₇₂ is hydrogen;

each of R₁₀ is independently-C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —OH, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-D, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl or —C₁₋₁₀alkyl-C₃₋₁₀aryl, each of which isunsubstituted or substituted by one or more independent R₁₁substituents;

R₂₁ is pyridyl selected from the group consisting of 2-pyridyl,3-pyridyl and 4-pyridyl, which is unsubstituted or substituted by one ormore independent R₁₂ substituents;

L is a bond;

R₄ is hydrogen;

R₅ is hydrogen; R₇₂ is hydrogen;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

The invention also provides a compound as defined above, wherein thecompound is of Formula II-E:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II-E, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II-E, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², —C₁₋₁₀alkyl, -L-C₁₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II-E, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; wherein the C₁₋₁₀hetaryl of R₂₁ comprises one or morenitrogen atoms; each R₁₂ substituent, when present, is independentlyselected from the group consisting of —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; whereineach R₃₁ is independently hydrogen or —C₁₋₁₀ alkyl; L is a bond; and R₁is —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-E, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; wherein the C₁₋₁₀hetaryl of R₂₁ comprises one or morenitrogen atoms; each R₁₂ substituent, when present, is independentlyselected from the group consisting of —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; wherein each R₃₁ isindependently hydrogen or —C₁₋₁₀ alkyl; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-E, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; wherein the C₁₋₁₀hetaryl of R₂₁ comprises one or morenitrogen atoms; each R₁₂ substituent, when present, is independentlyselected from the group consisting of —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; whereineach R₃₁ is independently hydrogen or —C₁₋₁₀alkyl; L is a bond; and R₁is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-E, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; the C₁₋₁₀hetaryl of R₂₁ is selected from the groupconsisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl; each R₁₂ substituent, when present, is independentlyselected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe,-OEt, -OPr; L is a bond; and R₁ is —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-E, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; the C₁₋₁₀hetaryl of R₂₁ is selected from the groupconsisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl; each R₁₂ substituent, when present, is independentlyselected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe,-OEt, -OPr; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-E, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; the C₁₋₁₀hetaryl of R₂₁ is selected from the groupconsisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl; each R₁₂ substituent, when present, is independentlyselected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe,-OEt, -OPr; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-E, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; the C₁₋₁₀hetaryl of R₂₁ is selected from the groupconsisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl; each R₁₂ substituent, when present, is independentlyselected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe,-OEt, -OPr; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-E, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II-E, R₇₂ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, R₇₂ is independently hydrogen.

In some embodiments of Formula II-E, each of R₁₀ independently is—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁ substituents. Insome embodiments, each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents.

In some embodiments of Formula II-E, each of R₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula II-E, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-E,

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula II-E,

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula II-E,

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and each of R³¹ and R³² is independentlyhydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-E,

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH, —CF₃, —OR³¹ or —CN; and each of R³¹ is independently hydrogen or—C₁₋₁₀ alkyl.

In some embodiments of Formula II-E,

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, or—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is -L-C₃₋₁₀aryl or -L-C₁₋₁₀hetaryl, each of which is unsubstitutedor substituted by one or more independent R₁₂ substituents;

L is a bond or —N(R³¹)—;

R₇₂ is hydrogen;

each of R₁₀ is independently-C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —OH, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-E,

R₁ is —C₁₋₁₀alkyl or —C₁₋₁₀alkyl-C₃₋₁₀aryl, each of which isunsubstituted or substituted by one or more independent R₁₁substituents;

R₂₁ is pyridyl selected from the group consisting of 2-pyridyl,3-pyridyl and 4-pyridyl, which is unsubstituted or substituted by one ormore independent R₁₂ substituents;

L is a bond;

R₇₂ is hydrogen;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

The invention further provides a compound as defined above, wherein thecompound is of Formula II-F:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II-F, Y is CR₅, X₄ is N or CR₄. In someembodiments of Formula II-F, Y is CR₅, X₄ is N or CR₄. In someembodiments of Formula II-F, Y is CR₅, X₄ is CR₄.

In some embodiments of Formula II-F, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II-F, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II-F, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II-F, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula II-F, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula II-F, R₇₂ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, R₇₂ is independently hydrogen.

In some embodiments of Formula II-F, each of R₁₀ independently is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents.

In some embodiments of Formula II-F, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula II-F, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-F, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which is unsubstitutedor substituted by one or more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula II-F, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,or —C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula II-F, Y is CR₅, X₄ is CR₄;

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,or —C₂₋₁₀alkynyl;

R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-F, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OHor —CF₃; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-F, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, or—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is -L-C₃₋₁₀aryl or -L-C₁₋₁₀hetaryl, each of which is unsubstitutedor substituted by one or more independent R₁₂ substituents;

L is a bond or —N(R³¹)—;

R₄ is hydrogen;

R₅ is hydrogen; R₇₂ is hydrogen;

each of R₁₀ is independently-C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —OH, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-F, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl or —C₁₋₁₀alkyl-C₃₋₁₀aryl, each of which isunsubstituted or substituted by one or more independent R₁₁substituents;

R₂₁ is pyridyl selected from the group consisting of 2-pyridyl,3-pyridyl and 4-pyridyl, which is unsubstituted or substituted by one ormore independent R₁₂ substituents;

L is a bond;

R₄ is hydrogen;

R₅ is hydrogen; R₇₂ is hydrogen;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

The invention further provides a compound as defined above, wherein thecompound is of Formula II-G:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula II-G, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula II-G, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula II-G, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; wherein the C₁₋₁₀hetaryl of R₂₁ comprises one or morenitrogen atoms; each R₁₂ substituent, when present, is independentlyselected from the group consisting of —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; whereineach R₃₁ is independently hydrogen or —C₁₋₁₀ alkyl; L is a bond; and R₁is —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-G, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; wherein the C₁₋₁₀hetaryl of R₂₁ comprises one or morenitrogen atoms; each R₁₂ substituent, when present, is independentlyselected from the group consisting of —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; whereineach R₃₁ is independently hydrogen or —C₁₋₁₀ alkyl; L is a bond; and R₁is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-G, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; wherein the C₁₋₁₀hetaryl of R₂₁ comprises one or morenitrogen atoms; each R₁₂ substituent, when present, is independentlyselected from the group consisting of —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₁₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; wherein each R₃₁ isindependently hydrogen or —C₁₋₁₀ alkyl; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-G, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; wherein the C₁₋₁₀hetaryl of R₂₁ comprises one or morenitrogen atoms; each R₁₂ substituent, when present, is independentlyselected from the group consisting of —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₁₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; wherein each R₃₁ isindependently hydrogen or —C₁₋₁₀alkyl; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-G, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; the C₁₋₁₀hetaryl of R₂₁ is selected from the groupconsisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl; each R₁₂ substituent, when present, is independentlyselected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe,-OEt, -OPr; L is a bond; and R₁ is —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₁₋₁₀aryl, unsubstituted or substituted by one ormore independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula II-G, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; the C₁₋₁₀hetaryl of R₂₁ is selected from the groupconsisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl; each R₁₂ substituent, when present, is independentlyselected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe,-OEt, -OPr; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-G, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; the C₁₋₁₀hetaryl of R₂₁ is selected from the groupconsisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl; each R₁₂ substituent, when present, is independentlyselected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe,-OEt, -OPr; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-G, R₂₁ is -L-C₁₋₁₀hetarylunsubstituted or substituted by one or more independent R₁₂substituents; the C₁₋₁₀hetaryl of R₂₁ is selected from the groupconsisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl; each R₁₂ substituent, when present, is independentlyselected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe,-OEt, -OPr; L is a bond; and R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In some embodiments of Formula II-G, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, Or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula II-G, R₇₂ is hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, R₇₂ is independently hydrogen.

In some embodiments of Formula II-G, each of R₁₀ independently is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents.

In some embodiments of Formula II-G, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula II-G, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-G;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula II-G,

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula II-G;

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-G;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OHor —CF₃; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-G;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, or—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is -L-C₃₋₁₀aryl or -L-C₁₋₁₀hetaryl, each of which is unsubstitutedor substituted by one or more independent R₁₂ substituents;

L is a bond or —N(R³¹)—;

R₇₂ is hydrogen;

each of R₁₀ is independently-C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —OH, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula II-G;

R₁ is —C₁₋₁₀alkyl or —C₁₋₁₀alkyl-C₃₋₁₀aryl, each of which isunsubstituted or substituted by one or more independent R₁₁substituents;

R₂₁ is pyridyl selected from the group consisting of 2-pyridyl,3-pyridyl and 4-pyridyl, which is unsubstituted or substituted by one ormore independent R₁₂ substituents;

L is a bond;

each of R₁₁ and R₁₂ is independently halogen, —C₁₋₁₀alkyl, —CF₃ or—OR³¹; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

The invention also provides a compound as defined above, wherein thecompound is of Formula III:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula III, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is CR₃R₃′. In some embodiments, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, andX₃ is C═O. In some embodiments, X₁ is C═S, X₂ is CR₁R₁′, and X₃ isCR₃R₃′. In some embodiments, X₁ is SO₂, X₂ is NR₁₂, and X₃ is CR₃R₃′. Insome embodiments, X₁ is SO₂, and X₂ and X₃ is R₁C═CR₃.

In some embodiments of Formula III, Y is CR₅, X₄ is N or CR₄, X₅ is Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is N or CR₄, X₅ is N or Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ isC. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N and X₆ is C. Insome embodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is N.

In some embodiments of Formula III, X₇ is CR₇₁, X₈ is N, X₉ is CR₂₁, andX₁₀ is N. In some embodiments, X₇ is CR₇₁, X₈ is N, X₉ is CR₂₁, and X₁₀is CR₉₁. In some embodiments, X₇ is NR₇₂, X₈ is CR₈₁, X₉ is CR₂₁, andX₁₀ is N. In some embodiments, X₇ is NR₇₂, X₈ is CR₈, X₉ is CR₂₁, andX₁₀ is CR₉₁. In some embodiments, X₇ is CR₇₁, X₈ is CR₈, X₉ is NR₂₂, andX₁₀ is N. In some embodiments, X₇ is CR₇₁, X₈ is CR₈₁, X₉ is NR₂₂, andX₁₀ is CR₉₁.

In some embodiments of Formula III, X₁ is C═O or SO₂, X₂ is NR₁ orCR₁R₁′, X₃ is CR₃R₃′ or C═O, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆is C, X₇ is N or NR₇ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₂ or CR₂₁, andX₁₀ is N or CR₁. In some embodiments, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃is CR₃R₃′, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂or CR₇₁, X₈ is N, X₉ is NR₂₂ or CR₂₁, and X₁₀ is N or CR₁. In someembodiments, X₁ is C═O, X₂ is NR₁, X₃ is CR₃R₃′, Y is CR₅, X₄ is CR₄, X₅is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁, and X₁₀ is N or CR₉₁.

In some embodiments of Formula III, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents

In some embodiments of Formula III, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁′ is hydrogen,—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula III, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments on Formula III, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula III, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. In someembodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—,—OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In some embodiments, L is abond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In some embodiments, Lis a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula III, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula III, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃′ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula III, R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶,—C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring. Insome embodiments, R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶together with R³⁴ can optionally form aheterocyclic ring. In some embodiments, R₃′ is —OR⁶ or —NR⁶R³⁴, whereinR⁶ together with R³⁴ can optionally form a heterocyclic ring.

In some embodiments of Formula III, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula III, R₅ is hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In someembodiments, R₅ is hydrogen.

In some embodiments of Formula III, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula III, each of R₇₁, R₈₁ and R₉₁ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹or —NR³¹C(═O)R³². In some embodiments, each of R₇₁, R₈₁ and R₉₁ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₇₁, R₈₁ and R₉₁ is independently hydrogen,halogen, or —C₁₋₁₀alkyl. In some embodiments, each of R₇₁, R₈₁ and R₉₁is independently hydrogen.

In some embodiments of Formula III, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, each of R₇₂, R₈₂ andR₉₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, each of R₇₂, R₈₂ and R₉₂ is independently hydrogen or—C₁₋₁₀alkyl. In some embodiments, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen.

In some embodiments of Formula III, each of R₁₀ and R₁₄ is independently—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substitutedby one or more independent R₁₁ substituents.

In some embodiments of Formula III, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula III, each of R³¹, R³² and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³² and R³⁴ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula III, X₁ is C═O or SO₂, X₂ is NR₁ orCR₁R₁′, X₃ is CR₃R₃′ or C═O, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₂ or CR₂₁, andX₁₀ is N or CR₉₁;

R₁ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁, R₈₁ and R₉₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, or —C(═O)SR³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula III, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, X₃is CR₃R₃′, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂or CR₇₁, X₈ is N, X₉ is NR₂₂ or CR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁ and R₉₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, or —C(═O)SR³¹ each of R₁₀and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula III, X₁ is C═O, X₂ is NR₁₂, X₃ is CR₃R₃′,Y is C_(R) X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁,and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴, —S(O)₀₋₂R⁶,—C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶,wherein R⁶ together with R³⁴ can optionally form a heterocyclic ring;

each of R₅ and R₉₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, or—OH;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹,

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl; andwherein ring A comprises one or more heteroatoms selected from N, O, orS.

In some embodiments of Formula III, X₁ is C═O, X₂ is NR₁₂, X₃ is CR₃R₃′,Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁,and X₁₀ is N;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃;

each of R³¹ and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl; and

wherein ring A comprises one or more heteroatoms selected from N, O, orS.

The invention also provides a compound as defined above, wherein thecompound is of Formula III-A:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula III-A, Y is CR₅, X₄ is N or CR₄, X₅ is Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N or C andX₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is C.In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N and X₆ is C. In someembodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is N.

In some embodiments of Formula III-A, X₇ is CR₇₁, X₈ is N, X₉ is CR₂₁,and X₁₀ is N. In some embodiments, X₇ is CR₇₁, X₈ is N, X₉ is CR₂₁, andX₁₀ is CR₉₁. In some embodiments, X₇ is NR₇₂, X₈ is CR₈₁, X₉ is CR₂₁,and X₁₀ is N. In some embodiments, X₇ is NR₇₂, X₈ is CR₈₁, X₉ is CR₂₁,and X₁₀ is CR₉₁. In some embodiments, X₇ is CR₇₁, X₈ is CR₈₁, X₉ isNR₂₂, and X₁₀ is N. In some embodiments, X₇ is CR₇₁, X₈ is CR₈₁, X₉ isNR₂₂, and X₁₀ is CR₉₁.

In some embodiments of Formula III-A, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₁ orCR₂₁, and X₁₀ is N or CR₉₁. In some embodiments, Y is CR₅, X₄ is N orCR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, X₉ is NR₂₂ orCR₂₁, and X₁₀ is N or CR₉₁. In some embodiments, Y is CR₅, X₄ is CR₄, X₅is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁, and X₁₀ is N or CR₉₁.

In some embodiments of Formula III-A, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula III-A, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, hydrogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments on Formula III-A, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula III-A, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula III-A, R₄ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula III-A, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula III-A, each of R₇₁, R₈₁ and R₉₁ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³².In some embodiments, each of R₇₁, R₈₁ and R₉₁ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, each of R₇₁, R₈₁ and R₉₁ isindependently hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments,each of R₇₁, R₈₁ and R₉₁ is independently hydrogen.

In some embodiments of Formula III-A, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, each of R₇₂, R₈₂ andR₉₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, each of R₇₂, R₈₂ and R₉₂ is independently hydrogen or—C₁₋₁₀alkyl. In some embodiments, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen.

In some embodiments of Formula III-A, each of R₁₀ independently is—C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents.

In some embodiments of Formula III-A, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula III-A, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula III-A, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₂ orCR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, eachof which is unsubstituted or substituted by one or more independent R₁₃substituents;

each of R₅, R₇₁, R₈₁ and R₉₁ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²;

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈, X₉ and X₁₀ is a heteroatomselected from N, O, or S.

In some embodiments of Formula III-A, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, X₉ is NR₂₂ or CR₂₁, and X₁₀is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents;

each of R₅, R₇₁ and R₉₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, or —C(═O)SR³¹;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈, X₉ and X₁₀ is a heteroatomselected from N, O, or S.

In some embodiments of Formula III-A, Y is CR₅, X₄ is CR₄, X₅ is C, X₆is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl;

each of R₅ and R₉₁ is independently hydrogen, halogen, or —C₁₋₁₀ alkyl,

R₇₂ is hydrogen or —C₁₋₁₀ alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹,

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl; and

wherein at least one of X₅, X₆, X₇, X₈, X₉ and X₁₀ is a heteroatomselected from N, O, or S.

In some embodiments of Formula III-A, Y is CR₅, X₄ is CR₄, X₅ is C, X₆is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁, and X₁₀ is N;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH or —CF₃;

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl; and

wherein at least one of X₅, X₆, X₇, X₈, X₉ and X₁₀ is a heteroatomselected from N, O, or S.

The invention also provides a compound as defined above, wherein thecompound is of Formula III-B:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula III-B, Y is CR₅, X₄ is N or CR₄, X₅ is Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N or C andX₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is C.In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N and X₆ is C. In someembodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is N.

In some embodiments of Formula III-B, X₇ is CR₇₁, X₈ is N, X₉ is CR₂₁,and X₁₀ is N. In some embodiments, X₇ is CR₇₁, X₈ is N, X₉ is CR₂₁, andX₁₀ is CR₉₁. In some embodiments, X₇ is NR₇₂, X₈ is CR₈₁, X₉ is CR₂₁,and X₁₀ is N. In some embodiments, X₇ is NR₇₂, X₈ is CR₈₁, X₉ is CR₂₁,and X₁₀ is CR₉₁. In some embodiments, X₇ is CR₇₁, X₈ is CR₈₁, X₉ isNR₂₂, and X₁₀ is N. In some embodiments, X₇ is CR₇₁, X₈ is CR₈₁, X₉ isNR₂₂, and X₁₀ is CR₉₁.

In some embodiments of Formula III-B, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₁ orCR₂₁, and X₁₀ is N or CR₉₁. In some embodiments, Y is CR₅, X₄ is N orCR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, X₉ is NR₂₂ orCR₂₁, and X₁₀ is N or CR₉₁. In some embodiments, Y is CR₅, X₄ is CR₄, X₅is C, X₆ is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁, and X₁₀ is N or CR₉₁.

In some embodiments of Formula III-B, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀ alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula III-B, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, hydrogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments on Formula III-B, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula III-B, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula III-B, R₄ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula III-B, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula III-B, each of R₇₁, R₈₁ and R₉₁ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³².In some embodiments, each of R₇₁, R₈₁ and R₉₁ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, each of R₇₁, R₈₁ and R₉₁ isindependently hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments,each of R₇₁, R₈₁ and R₉₁ is independently hydrogen.

In some embodiments of Formula III-B, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, each of R₇₂, R₈₂ andR₉₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, each of R₇₂, R₈₂ and R₉₂ is independently hydrogen or—C₁₋₁₀alkyl. In some embodiments, each of R₇₂, R₈₂ and R₉₂ isindependently hydrogen.

In some embodiments of Formula III-B, each of R₁₀ independently is—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents.

In some embodiments of Formula III-B, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃.

In some embodiments of Formula III-B, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula III-B, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, X₉ is NR₂₂ orCR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, eachof which is unsubstituted or substituted by one or more independent R₁₃substituents;

each of R₅, R₇₁, R₈₁ and R₉₁ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²;

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈, X₉ and X₁₀ is a heteroatomselected from N, O, or S.

In some embodiments of Formula III-B, Y is CR₅, X₄ is N or CR₄, X₅ is Nor C, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, X₉ is NR₂₂ or CR₂₁, and X₁₀is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents;

each of R₅, R₇₁ and R₉₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, or —C(═O)SR³¹ each of R₁₀is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈, X₉ and X₁₀ is a heteroatomselected from N, O, or S.

In some embodiments of Formula III-B, Y is CR₅, X₄ is CR₄, X₅ is C, X₆is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁, and X₁₀ is N or CR₉₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl;

each of R₅ and R₉₁ is independently hydrogen, halogen, or —C₁₋₁₀ alkyl,R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹,

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl; and

wherein at least one of X₅, X₆, X₇, X₈, X₉ and X₁₀ is a heteroatomselected from N, O, or S.

In some embodiments of Formula III-B, Y is CR₅, X₄ is CR₄, X₅ is C, X₆is C, X₇ is NR₇₂, X₈ is N, X₉ is CR₂₁, and X₁₀ is N;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH or —CF₃;

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl; and

wherein at least one of X₅, X₆, X₇, X₈, X₉ and X₁₀ is a heteroatomselected from N, O, or S.

The invention also provides a compound of Formula IV-A:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula IV-A, X₁ is C═O and X₂ is NR₁ or CR₁R₁′.In some embodiments, X₁ is C═O and X₂ is NR₁ or CR₁R₁′. In someembodiments, X₁ is C═S and X₂ is CR₁. In some embodiments, X₁ is SO₂ andX₂ is NR₁.

In some embodiments of Formula IV-A, Y is CR₅, X₄ is N or CR₄, X₅ is Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N or C andX₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is C.In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N and X₆ is C. In someembodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is N.

In some embodiments of Formula IV-A, X₇ is NH, X₈ is N and X₉ is CR₂₁.In some embodiments, X₇ is N and X₈ is CR₁ and X₉ is CR₂₁. In someembodiments, X₇ is CR₇, X₈ is N and X₉ is NR₂₂. In some embodiments, X₇is CR₇, X₈ is N and X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is Nand X₉ is CR₂. In some embodiments, X₇ is O, X₈ is CR₈₁ and X₉ is NR₂₁.

In some embodiments of Formula IV-A, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, Yis N or CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is N or NR₇₂ orCR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂ or CR₂₁. In some embodiments, X₁is C═O, X₂ is NR₁ or CR₁R₁′, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₂ or CR₂₁. In someembodiments, X₁ is C═O, X₂ is NR₁, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ isC, X₇ is NR₇₂, X₈ is N, and X₉ is CR₂₁.

In some embodiments of Formula IV-A, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula IV-A, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁′ is hydrogen,—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula IV-A, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments on Formula IV-A, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula IV-A, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula IV-A, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-A, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula IV-A, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀ hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula IV-A, each of R₇₁ and R₈₁ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹or —NR³¹C(═O)R³². In some embodiments, each of R₇₁ and R₈₁ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₇₁ and R₈₁ is independently hydrogen, halogen, or—C₁₋₁₀alkyl. In some embodiments, each of R₇₁ and R₈₁ is independentlyhydrogen.

In some embodiments of Formula IV-A, each of R₇₂ and R₈₂ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, each of R₇₂ and R₈₂ isindependently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, eachof R₇₂ and R₈₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, each of R₇₂ and R₈₂ is independently hydrogen

In some embodiments of Formula IV-A, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents. In some embodiments, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents. In some embodiments, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents.

In some embodiments of Formula IV-A, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula IV-A, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, orwherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², and R³³ is independently hydrogenor —C₁₋₁₀alkyl.

In some embodiments of Formula IV-A, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, Yis CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁,X₈ is N or CR₈₁, and X₉ is NR₂₂ or CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which is unsubstitutedor substituted by one or more independent R₁₃ substituents;

each of R₅, R₇₁, and R₈₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula IV-A, X₁ is C═O, X₂ is NR₁ or CR₁R₁′, Yis CR₅, X₄ is N or CR₄, X₅ is N or C, X₆ is C, X₇ is NR₇₂ or CR₇₁, X₈ isN, and X₉ is NR₂₁ or CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents;

each of R₅ and R₇₁ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and each of R³¹ and R³² isindependently hydrogen or —C₁₋₁₀alkyl, or wherein R³¹ together with R³²form a heterocyclic ring.

In some embodiments of Formula IV-A, X₁ is C═O, X₂ is NR₁, Y is CR₅, X₄is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉ is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl;

R₅ is independently hydrogen, halogen, or —C₁₋₁₀alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula IV-A, X₁ is C═O, X₂ is NR₁, Y is CR₅, X₄is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉ is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

The invention also provides a compound as defined above, wherein thecompound is of Formula IV-B:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula IV-B, X₁ is C═O and X₂ is NR₁ or CR₁R₁′.In some embodiments, X₁ is C═O and X₂ is NR₁ or CR₁R₁′. In someembodiments, X₁ is C═S and X₂ is CR₁. In some embodiments, X₁ is SO₂ andX₂ is NR₁.

In some embodiments of Formula IV-B, X₁ is C═O or SO₂, X₂ is NR₁ orCR₁R₁′, Y is CR₅, and X₄ is N or CR₄. In some embodiments, X₁ is C═O orSO₂, X₂ is NR₁ or CR₁R₁′, Y is CR₅ and X₄ is N or CR₄. In someembodiments, X₁ is C═O, X₂ is NR₁, Y is CR₅ and X₄ is CR₄.

In some embodiments of Formula IV-B, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula IV-B, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁′ is hydrogen,—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula IV-B, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², —C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula IV-B, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula IV-B, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-B, R₅ is hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀ alkyl. In someembodiments, R₅ is hydrogen.

In some embodiments of Formula IV-B, R₇₂ is hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, R₇₂is hydrogen or —C₁₋₁₀alkyl. In some embodiments, R₇₂ is hydrogen.

In some embodiments of Formula IV-B, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents. In some embodiments, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents. In some embodiments, each of R₁₀ and R₁₄ isindependently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents.

In some embodiments of Formula IV-B, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula IV-B, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, orwherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², R³³ and R³⁴ is independentlyhydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-B, X₁ is C═O or SO₂, X₂ is NR₁ orCR₁R₁′, Y is CR₅ and X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃-cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which is unsubstitutedor substituted by one or more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula IV-B, X₁ is C═O or SO₂, X₂ is NR₁ orCR₁R₁′, X₃ is CR₃R₃′, Y is CR₅ and X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,or —C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula IV-B, X₁ is C═O, X₂ is NR₁, Y is CR₅ andX₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl;

R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen or —C₁₋₁₀ alkyl;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-B, X₁ is C═O, X₂ is NR₁, Y is CR₅, X₄is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl; or R₃′ is —OR⁶ or—NR⁶R³⁴, wherein R⁶ together with R³⁴ can optionally form a heterocyclicring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH or —CF₃; and each of R³¹ is independently hydrogen or—C₁₋₁₀alkyl.

The invention also provides a compound as defined above, wherein thecompound is of Formula IV-C:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula IV-C, Y is CR₅, X₄ is N or CR₄. In someembodiments of Formula IV-C, Y is CR₅, X₄ is N or CR₄. In someembodiments of Formula IV-C, Y is CR₅, X₄ is CR₄.

In some embodiments of Formula IV-C, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula IV-C, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂ substituents

In some embodiments of Formula IV-C, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula IV-C, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹, R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-C, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula IV-C, R₇₂ is hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, R₇₂ is independently hydrogen.

In some embodiments of Formula IV-C, each of R₁₀ independently is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents

In some embodiments of Formula IV-C, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃

In some embodiments of Formula IV-C, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-C, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which is unsubstitutedor substituted by one or more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula IV-C, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂, is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₄ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,or —C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula IV-C, Y is CR₅, X₄ is CR₄;

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl;

R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³ or —NR¹C(═O)R²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-C, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH or —CF₃; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

The invention also provides a compound as defined above, wherein thecompound is of Formula IV-D:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula IV-D, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula IV-D, R₂₁ is hydrogen, halogen, —OH,—CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula IV-D, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula IV-D, R₇₂ is hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is hydrogen or —C₁₋₁₀alkyl. In some embodiments, R₇₂ ishydrogen.

In some embodiments of Formula IV-D, each of R₁₀ independently is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents

In some embodiments of Formula IV-D, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃

In some embodiments of Formula IV-D, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-D,

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀ ₋₂N(R³¹)—;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁ ₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring

In some embodiments of Formula IV-D,

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula IV-D,

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula IV-D,

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OHor —CF₃; and

each of R³¹ is independently hydrogen or —C₁₋₁₀alkyl.

The invention also provides a compound of Formula V-A:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula V-A, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, and X₃ is CR₃R₃′. In some embodiments, X₁ is C═O, Z isNR₁ or CR₁R₁′, X₂ is NR₁ or CR₁R₁′, and X₃ is C═O. In some embodiments,X₁ is C═S, Z is NR₁ or CR₁R₁′, X₂ is CR₁, and X₃ is CR₃R₃′. In someembodiments, X₁ is SO₂, Z is NR₁ or CR₁R₁′, X₂ is NR₁, and X₃ isCR₃R_(3′.)

In some embodiments of Formula V-A, Y is CR₅, X₄ is N or CR₄, X₅ is Cand X₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N or C andX₆ is C. In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is C.In some embodiments, Y is CR₅, X₄ is CR₄, X₅ is N and X₆ is C. In someembodiments, Y is CR₅, X₄ is CR₄, X₅ is C and X₆ is N.

In some embodiments of Formula V-A, X₇ is NH, X₈ is N and X₉ is CR₂₁. Insome embodiments, X₇ is N and X₈ is CR₈₁ and X₉ is CR₂₁. In someembodiments, X₇ is CR₇, X₈ is N and X₉ is NR₂₂. In some embodiments, X₇is CR₇, X₈ is N and X₉ is CR₂₁. In some embodiments, X₇ is O, X₈ is Nand X₉ is CR₂. In some embodiments, X₇ is O, X₈ is CR₈₁ and X₉ is NR₂₁.

In some embodiments of Formula V-A, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, X₃ is CR₃R₃′ or C═O, Y is N or CR₅, X₄ is N or CR₄, X₅ isN or C, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ isNR₂₂ or CR₂₁. In some embodiments, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, X₃ is CR₃R₃′, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₂ or CR₂₁. In someembodiments, X₁ is C═O, Z is CR₁R₁′, X₂ is NR₁, X₃ is CR₃R₃′, Y is CR₅,X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉ is CR₂₁. Insome embodiments, X₁ is C═O, Z is NR₁, X₂ is CR₁R₁′, X₃ is CR₃R₃′, Y isCR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇ is NR₇₂, X₈ is N, and X₉ is CR₂₁.

In some embodiments of Formula V-A, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula V-A, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁′ is hydrogen,—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula V-A, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₂ substituents.In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents

In some embodiments on Formula V-A, R₂₂ is hydrogen, —OH, —CF₃,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl,-L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents

In some embodiments of Formula V-A, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula V-A, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula V-A, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —C₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃′ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula V-A, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula V-A, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula V-A, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula V-A, each of R₇₁ and R₈₁ is independentlyhydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³².In some embodiments, each of R₇₁ and R₈₁ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, each of R₇₁ and R₈₁ is independentlyhydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, each of R₇₁ andR₈₁ is independently hydrogen.

In some embodiments of Formula V-A, each of R₇₂ and R₈₂ is independentlyhydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or—S(O)₀₋₂R³¹. In some embodiments, each of R₇₂ and R₈₂ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, each of R₇₂ and R₈₂ isindependently hydrogen or —C₁₋₁₀alkyl. In some embodiments, each of R₇₂and R₈₂ is independently hydrogen

In some embodiments of Formula V-A, each of R₁₀ and R₁₄ is independently—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substitutedby one or more independent R₁₁ substituents.

In some embodiments of Formula V-A, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula V-A, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl,or wherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², and R³³ is independently hydrogenor —C₁₋₁₀alkyl.

In some embodiments of Formula V-A, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, X₃ is CR₃R₃′ or C═O, Y is CR₅, X₄ is N or CR₄, X₅ is N orC, X₆ is C, X₇ is N or NR₇₂ or CR₇₁, X₈ is N or CR₈₁, and X₉ is NR₂₂ orCR₂₁, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is hydrogen, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,-L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅, R₇₁, and R₈, is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula V-A, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, X₃ is CR₃R₃′, Y is CR₅, X₄ is N or CR₄, X₅ is N or C, X₆is C, X₇ is NR₇₂ or CR₇₁, X₈ is N, and X₉ is NR₂₁ or CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

R₂₂ is —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹,-L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

each of R₅ and R₇₁ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

each of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl, orwherein R³¹ together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula V-A, X₁ is C═O, Z is NR₁ or CR₁R₁, X₂ isNR₁ or CR₁R₁′, X₃ is CR₃R₃′, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇is NR₇₂, X₈ is N, and X₉ is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴,—C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is independently hydrogen, halogen, or —C₁₋₁₀alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹ each of R³¹, R³²and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl, or wherein R³¹together with R³² form a heterocyclic ring; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

In some embodiments of Formula V-A, X₁ is C═O, Z is NR₁ or CR₁R₁, X₂ isNR₁ or CR₁R₁′, X₃ is CR₃R₃′, Y is CR₅, X₄ is CR₄, X₅ is C, X₆ is C, X₇is NR₇₂, X₈ is N, and X₉ is CR₂₁;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃ ₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH or —CF₃;

each of R³¹ and R³⁴ is independently hydrogen or —C₁₋₁₀ alkyl; and

wherein at least one of X₅, X₆, X₇, X₈ or X₉ comprises one or moreheteroatoms selected from N, O, or S.

The invention also provides a compound as defined above, wherein thecompound is of Formula V-B:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula V-B, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, and X₃ is CR₃R₃′. In some embodiments, X₁ is C═O, Z isNR₁ or CR₁R₁′, X₂ is NR₁ or CR₁R₁′, and X₃ is C═O. In some embodiments,X₁ is C═S, Z is NR₁ or CR₁R₁′, X₂ is NR₁ or CR₁R₁′, and X₃ is CR₃. Insome embodiments, X₁ is SO₂, is NR₁ or CR₁R₁′, X₂ is NR₁ or CR₁R₁′, andX₃ is CR₃R_(3′.)

In some embodiments of Formula V-B, X₁ is C═O or SO₂, Z is NR₁ orCR₁R₁′, X₂ is NR₁ or CR₁R₁′, X₃ is CH or C═O, Y is CR₅, and X₄ is N orCR₄. In some embodiments, X₁ is C═O or SO₂, Z is N_(R) or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, X₃ is CH, Y is CR₅ and X₄ is N or CR₄. In someembodiments, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ is NR₁ or CR₁R₁′, X₃ isCH, Y is CR₅ and X₄ is CR₄.

In some embodiments of Formula V-B, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula V-B, R₁′ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁′ is hydrogen,—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents. In someembodiments, R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents.

In some embodiments of Formula V-B, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —C₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₂ substituents.In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents

In some embodiments of Formula V-B, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—

In some embodiments of Formula V-B, R₃ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula V-B, R₃′ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₃′ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₃′ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₃′is hydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula V-B, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃ substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula V-B, R₅ is hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀ alkyl. In someembodiments, R₅ is hydrogen.

In some embodiments of Formula V-B, R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents.

In some embodiments of Formula V-B, R₇₂ is hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In some embodiments, R₇₂is hydrogen or —C₁₋₁₀alkyl. In some embodiments, R₇₂ is hydrogen.

In some embodiments of Formula V-B, each of R₁₀ and R₁₄ is independently—C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ and R₁₄ is independently —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substitutedby one or more independent R₁₁ substituents.

In some embodiments of Formula V-B, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, R₁₃ and R₁₅ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃.

In some embodiments of Formula V-B, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², R³³ and R³⁴ isindependently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl,or wherein R³¹ together with R³² form a heterocyclic ring. In someembodiments, each of R³¹, R³², R³³ and R³⁴ is independently hydrogen or—C₁₋₁₀alkyl, or wherein R³¹ together with R³² form a heterocyclic ring.In some embodiments, each of R³¹, R³², R³³ and R³⁴ is independentlyhydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula V-B, X₁ is C═O or SO₂, Z is NR₁ orCR₁R₁′, X₂ is NR₁ or CR₁R₁′, X₃ is CR₃R₃′ or C═O, Y is CR₅ and X₄ is Nor CR₄;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁substituents;

R₁′ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents; or R₃′ is —OR⁶, —NR⁶R³⁴,—S(O)₀₋₂R⁶, —C(═O)R⁶, —C(═O)OR⁶, —OC(═O)R⁶, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —C₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;and

each of R³¹, R³² and R³⁴ is independently hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula V-B, X₁ is C═O or SO₂, Z is NR₁ orCR₁R₁′, X₂ is NR₁ or CR₁R₁′, X₃ is CR₃R₃′, Y is CR₅ and X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of whichis unsubstituted or substituted by one or more independent R₁₃substituents; or R₃′ is —OR⁶, —NR⁶R³⁴, —C(═O)N(R³⁴)R⁶, or—N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ can optionally form aheterocyclic ring;

R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³ or —NR³¹C(═O)R³²;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and each of R³¹, R³² and R³⁴ isindependently hydrogen or —C₁₋₁₀alkyl, or wherein R³¹ together with R³²form a heterocyclic ring.

In some embodiments of Formula V-B, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, X₃ is CR₃R₃′, Y is CR₅ and X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl; or R₃′ is —OR⁶, —NR⁶R³⁴,—C(═O)N(R³⁴)R⁶, or —N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₄ or R₁₅ substituents;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂, R₁₃ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or —S(O)₀₋₂R³¹; andeach of R³¹, R³² and R³⁴ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula V-B, X₁ is C═O, Z is NR₁ or CR₁R₁′, X₂ isNR₁ or CR₁R₁′, X₃ is CR₃R₃′, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃, R₃′ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl; or R₃′ is —OR⁶ or —NR⁶R³⁴, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

R₅ is hydrogen;

R₆ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₄ orR₁₅ substituents;

R₇₂ is hydrogen;

each of R₁₀ and R₁₄ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents;

each of R₁₁, R₁₂ and R₁₅ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH or —CF₃; and each of R³¹ and R³⁴ is independentlyhydrogen or —C₁₋₁₀ alkyl.

The invention also provides a compound as defined above, wherein thecompound is of Formula V-C:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula V-C, Y is CR₅, and X₄ is N or CR₄. Insome embodiments of Formula V-C, Y is CR₅, and X₄ is CR₄.

In some embodiments of Formula V-C, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula V-C, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula V-C, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula V-C, R₄ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted by oneor more independent R₁₃ substituents. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or—C₂₋₁₀alkynyl, each of which is unsubstituted or substituted by one ormore independent R₁₃substituents. In some embodiments, R₄ is hydrogen,halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl. In some embodiments, R₄ ishydrogen, halogen, —OH, —CF₃, or —C₁₋₁₀alkyl.

In some embodiments of Formula V-C, R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂,—CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen,halogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³². In some embodiments, R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl. In some embodiments, R₅ is hydrogen.

In some embodiments of Formula V-C, R₇₂ is hydrogen, —C₁₋₁₀alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, R₇₂ is independently hydrogen.

In some embodiments of Formula V-C, each of R₁₀ independently is—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,optionally substituted by one or more independent R₁₁ substituents. Insome embodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents.

In some embodiments of Formula V-C, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —OH or —CF₃.

In some embodiments of Formula V-C, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula V-C, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, eachof which is unsubstituted or substituted by one or more independent R₁₃substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula V-C, Y is CR₅, X₄ is N or CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl, each of which isunsubstituted or substituted by one or more independent R₁₃substituents;

R₅ is hydrogen, halogen, —C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independent R₁substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring.

In some embodiments of Formula V-C, Y is CR₅, X₄ is CR₄;

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, or —C₂₋₁₀alkynyl;

R₅ is hydrogen, halogen, or —C₁₋₁₀alkyl;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula V-C, Y is CR₅, X₄ is CR₄;

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

each of R₃ and R₄ is independently hydrogen, halogen, —OH, —CF₃, or—C₁₋₁₀alkyl;

R₅ is hydrogen;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀ alkyl,—OH or —CF₃; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

The invention also provides a compound as defined above, wherein thecompound is of Formula V-D:

or a pharmaceutically acceptable salt or prodrug thereof, and whereinthe substituents are as defined above.

In some embodiments of Formula V-D, R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁ substituents.

In some embodiments of Formula V-D, R₂₁ is hydrogen, halogen, —OH, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl,-L-C₂₋₁₀alkynyl, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OCF₃,—OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹,—NR³¹C(═O)R³², -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents. In some embodiments, R₂₁ is halogen, —OH, —CF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ ishalogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents.

In some embodiments of Formula V-D, L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—. Insome embodiments, L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—,—C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. In someembodiments, L is a bond, —N(R³¹)—, —C(═O)N(R³¹)—, or —N(R³¹)C(═O)—. Insome embodiments, L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—.

In some embodiments of Formula V-D, R₇₂ is hydrogen, —C₁₋₁₀ alkyl,—C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH,—CF₃, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, or —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is independently hydrogen or —C₁₋₁₀alkyl. In someembodiments, R₇₂ is independently hydrogen.

In some embodiments of Formula V-D, each of R₁₀ independently is —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀ alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionallysubstituted by one or more independent R₁₁ substituents. In someembodiments, each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl, optionally substituted by one ormore independent R₁₁ substituents

In some embodiments of Formula V-D, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³². In someembodiments, each of R₁₁, R₁₂, and R₁₃ is independently hydrogen,halogen, —C₁₋₁₀ alkyl, —OH, —CF₃, —OR³, —NR³¹R³², —NO₂, —CN, or—S(O)₀₋₂R³¹. In some embodiments, each of R₁₁, R₁₂, and R₁₃ isindependently hydrogen, halogen, —C₁₋₁₀alkyl, —OH or —CF₃.

In some embodiments of Formula V-D, each of R³¹, R³², and R³³ isindependently hydrogen, halogen, —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, or wherein R³¹ together with R³² form a heterocyclicring. In some embodiments, each of R³¹, R³², and R³³ is independentlyhydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, or —C₃₋₁₀cycloalkyl, or wherein R³¹together with R³² form a heterocyclic ring. In some embodiments, each ofR³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring. In some embodiments,each of R³¹, R³², and R³³ is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula V-D,

R₁ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,each of which is unsubstituted or substituted by one or more independentR₁₀ or R₁₁ substituents;

R₂₁ is hydrogen, halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³²,-L-C₁₋₁₀alkyl, -L-C₂₋₁₀alkenyl, -L-C₂₋₁₀alkynyl, -L-C₃₋₁₀aryl,-L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each ofwhich is unsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, —N(R³¹)C(═O)—, —NR³¹C(═O)O—, —NR³¹C(═O)NR³²—,—NR³¹S(O)₀₋₂—, or —S(O)₀₋₂N(R³¹)—;

R₇₂ is hydrogen, —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, or —S(O)₀₋₂R³¹;

each of R₁₀ is independently —C₁₋₁₀ alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,or —C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —OH, —CF₃, —OCF₃, —OR³¹,—NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹ or—NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl,or —C₃₋₁₀cycloalkyl, or wherein R³¹ together with R³² form aheterocyclic ring.

In some embodiments of Formula V-D,

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₃₋₁₀cycloalkyl, —C(O)R³¹,—CO₂R³¹, —C(═O)NR³¹, —S(O)₀₋₂R³¹;

R₁₀ is —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁, R₁₂, and R₁₃ is independently hydrogen, halogen,—C₁₋₁₀alkyl, —OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹,—NO₂, —CN, —S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl, or whereinR³¹ together with R³² form a heterocyclic ring

In some embodiments of Formula V-D,

R₁ is C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁ substituents;

R₂₁ is halogen, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —NR³¹C(═O)R³², -L-C₁₋₁₀alkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents;

L is a bond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—;

R₇₂ is hydrogen or —C₁₋₁₀alkyl;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, optionally substituted by oneor more independent R₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl,—OH, —CF₃, —OR³¹, —NR³¹R³², —C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN,—S(O)₀₋₂R³¹ or —NR³¹C(═O)R³²; and

each of R³¹ and R³² is independently hydrogen or —C₁₋₁₀alkyl.

In some embodiments of Formula V-D,

R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, each ofwhich is unsubstituted or substituted by one or more independent R₁₀ orR₁₁substituents;

R₂₁ is halogen, —CN, -L-C₁₋₁₀alkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, or -L-C₁₋₁₀heterocyclyl, each of which isunsubstituted or substituted by one or more independent R₁₂substituents;

L is a bond, —N(R³¹)—, or —C(═O)N(R³¹)—;

R₇₂ is hydrogen;

each of R₁₀ is independently —C₁₋₁₀alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, or—C₁₋₁₀heterocyclyl, optionally substituted by one or more independentR₁₁ substituents;

each of R₁₁ and R₁₂ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —OHor —CF₃; and

each of R³¹ is independently hydrogen or —C₁₋₁₀ alkyl.

Additional embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D) are described below.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkyl, which is unsubstituted. In some embodiments, R₁is —C₁₋₁₀alkyl, substituted by one or more independent R₁₀ substituents.In some embodiments, R₁ is —C₁₋₁₀alkyl, substituted by one or moreindependent R₁₁ substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkenyl, which is unsubstituted. In some embodiments,R₁ is —C₁₋₁₀alkenyl, substituted by one or more independent R₁₀substituents. In some embodiments, R₁ is —C₁₋₁₀alkenyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀alkenyl, substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₂₋₁₀alkynyl, which is unsubstituted. In some embodiments,R₁ is —C₂₋₁₀alkynyl, substituted by one or more independent R₁₀substituents. In some embodiments, R₁ is —C₂₋₁₀alkynyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁ is—C₂₋₁₀alkynyl, substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀heteroalkyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heteroalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀heteroalkyl, substitutedby one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀aryl, which is unsubstituted. In some embodiments, R₁is —C₃₋₁₀aryl, substituted by one or more independent R₁₀ substituents.In some embodiments, R₁ is —C₃₋₁₀aryl, substituted by one or moreindependent R₁₁ substituents. In some embodiments, R₁ is —C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀hetaryl, which is unsubstituted. In some embodiments,R₁ is —C₁₋₁₀hetaryl, substituted by one or more independent R₁₀substituents. In some embodiments, R₁ is —C₁₋₁₀hetaryl, substituted byone or more independent R₁ substituents. In some embodiments, R₁ is—C₁₋₁₀hetaryl, substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀cycloalkyl, substitutedby one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀heterocyclyl, substitutedby one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀alkyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₂₋₁₀alkenyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₁ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁ is—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₁ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₂₋₁₀alkynyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II-A, II-B, II-C and II-D) and IIII(including III-A and III-B), R₁ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which isunsubstituted. In some embodiments, R₁ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, substituted by one ormore independent R₁₁ substituents. In some embodiments, R₁ is—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₀or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II-A, II-B, II-C and II-D) and IIII(including III-A and III-B), R₁ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, whichis unsubstituted. In some embodiments, R₁ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₀ substituents. In some embodiments, R₁ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀alkoxy-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, substituted by oneor more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀ heteroalkyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₁ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, substituted by oneor more independent R₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₁ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀aryl-C₁₋₁₀alkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀aryl-C₁₋₁₀alkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀aryl-C₂₋₁₀alkenyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀aryl-C₂₋₁₀alkynyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀aryl-C₃₋₁₀hetaryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, substituted by oneor more independent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀hetaryl-C₁₋₁₀alkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₁ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀hetaryl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₁ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₁ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₁ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₁ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁ is—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, substituted by oneor more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₁ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₁ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁ is—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is hydrogen.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkyl, which is unsubstituted. In some embodiments,R₁′ is —C₁₋₁₀alkyl, substituted by one or more independent R₁₀substituents. In some embodiments, R₁′ is —C₁₋₁₀alkyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkyl, substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkenyl, which is unsubstituted. In some embodiments,R₁′ is —C₁₋₁₀alkenyl, substituted by one or more independent R₁₀substituents. In some embodiments, R₁′ is —C₁₋₁₀alkenyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkenyl, substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₂₋₁₀alkynyl, which is unsubstituted. In some embodiments,R₁′ is —C₂₋₁₀alkynyl, substituted by one or more independent R₁₀substituents. In some embodiments, R₁′ is —C₂₋₁₀alkynyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkynyl, substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀heteroalkyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heteroalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀heteroalkyl, substitutedby one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀aryl, which is unsubstituted. In some embodiments,R₁′ is —C₃₋₁₀aryl, substituted by one or more independent R₁₀substituents. In some embodiments, R₁′ is —C₃₋₁₀aryl, substituted by oneor more independent R₁₁ substituents. In some embodiments, R₁′ is—C₃₋₁₀aryl, substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀hetaryl, which is unsubstituted. In some embodiments,R₁′ is —C₁₋₁₀hetaryl, substituted by one or more independent R₁₀substituents. In some embodiments, R₁′ is —C₁₋₁₀hetaryl, substituted byone or more independent R₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀hetaryl, substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₁′ is —C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀cycloalkyl, substitutedby one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀alkyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, substituted by oneor more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, substituted by one or more independent R₁substituents. In some embodiments, R₁′ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁′ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkenyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₁′ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₁′ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁′ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁′ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkynyl-C₃₋₁₀ aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₂₋₁₀alkynyl-C₃₋₁₀ aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II-A, II-B, II-C and II-D) and IIII(including III-A and III-B), R₁′ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which isunsubstituted. In some embodiments, R₁′ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁′ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, substituted by one ormore independent R₁₁ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₀or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II-A, II-B, II-C and II-D) and IIII(including III-A and III-B), R₁′ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, whichis unsubstituted. In some embodiments, R₁′ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₀ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁′ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkoxy-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, substituted by oneor more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₁′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which isunsubstituted. In some embodiments, R₁′ is—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₁′ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀aryl-C₁₋₁₀alkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀aryl-C₁₋₁₀alkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₁′ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀aryl-C₂₋₁₀alkenyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₁′ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀aryl-C₂₋₁₀alkynyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₁′ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀aryl-C₃₋₁₀hetaryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₁′ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁′ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀hetaryl-C₁₋₁₀alkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₁′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁′ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀hetaryl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, substituted by oneor more independent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, substituted by one ormore independent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁′ is—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₁′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, substituted byone or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, substituted by one or more independent R₁₁substituents. In some embodiments, R₁′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,substituted by one or more independent R₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heterocyclyl-C₁ ₋₁₀hetaryl, which is unsubstituted.In some embodiments, R₁′ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substitutedby one or more independent R₁₀ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₀ or R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₁′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₀ substituents. In someembodiments, R₁′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₁ substituents. In some embodiments, R₁′ is—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₀ or R₁₁ substituents.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E, II-F and II-G),Formula III (including Formula III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁ is —C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, unsubstituted or substituted by one ormore independent R₁₀ or R₁₁ substituents. In other embodiments, R₁ is—C₁₋₁₀alkyl, —C₁₋₁₀heterocyclyl, —C₁₋₁₀alkyl-C₃₋₁₀heterocyclyl,—C₁₋₁₀alkyl-C₃₋₁₀aryl, —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents. In yet other embodiments, R₁ is —C₁₋₁₀alkyl-C₃₋₁₀aryl,—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, unsubstituted or substituted by one ormore independent R₁₀ or R₁₁ substituents. In yet other embodiments, R₁is —C₁₋₁₀alkyl-C₃₋₁₀aryl or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, unsubstitutedor substituted

by one or more independent R₁₀ or R₁₁ substituents. In furtherembodiments, wherein R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents. In some embodiments, R1 is R₁ is —C₁₋₁₀heterocyclyl,—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, or —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents. In some embodiments, R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), each of R₁ or R₁′ is independently a substituent as shown below:

In further embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), each of R₁ or R₁′ is independently a substituent as shown below:

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula TV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is halogen, which is F, Cl, Br or I. In some embodiments, R₂₁is —OH. In some embodiments, R₂₁ is —CF₃. In some embodiments, R₂₁ is—OCF₃. In some embodiments, R₂₁ is —OR³¹. In some embodiments, R₂₁ is—NR³¹R³². In some embodiments, R₂₁ is —C(O)R³¹. In some embodiments, R₂₁is —CO₂R³¹. In some embodiments, R₂₁ is —C(═O)NR³¹. In some embodiments,R₂₁ is-NO₂. In some embodiments, R₂ is —CN. In some embodiments, R₂₁ is—S(O)₀₋₂R³¹. In some embodiments, R₂₁ is —SO₂NR³¹R³². In someembodiments, R₂₁ is —NR³¹C(═O)R³². In some embodiments, R₂₁ is—NR³¹C(═O)OR³². In some embodiments, R₂₁ is —NR³¹C(═O)NR³²R³³. In someembodiments, R₂₁ is —NR³¹S(O)₀₋₂R³². In some embodiments, R₂₁ is—C(═S)OR³¹. In some embodiments, R₂₁ is —C(═O)SR³¹. In some embodiments,R₂₁ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₂₁ is—NR³¹C(═NR³²)OR³³. In some embodiments, R₂₁ is —NR³¹C(═NR³²)SR³³. Insome embodiments, R₂₁ is —OC(═O)OR³³. In some embodiments, R₂₁ is—OC(═O)NR³¹R³². In some embodiments, R₂₁ is —OC(═O)SR³¹. In someembodiments, R₂₁ is —SC(═O)SR³¹. In some embodiments, R₂₁ is—P(O)OR³¹OR³². In some embodiments, R₂₁ is —SC(═O)NR³¹R³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀alkyl, which is unsubstituted. In some embodiments,R₂₁ is -L-C₁₋₁₀alkyl, which is substituted by one or more independentR₁₂ substituents. In some embodiments, R₂₁ is -L-C₁₋₁₀alkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀alkyl, which is substituted by one or more independent R₁₂substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₂₋₁₀alkenyl, which is unsubstituted and L is a bond. In someembodiments, R₂₁ is -L-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₂₋₁₀alkynyl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₂₋₁₀alkynyl, which is unsubstituted and L is a bond. In someembodiments, R₂₁ is -L-C₂₋₁₀alkynyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀heteroalkyl, which is unsubstituted and L is a bond. In someembodiments, R₂₁ is -L-C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₂ substituents, where L is a bond

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₁ is -L-C₃₋₁₀aryl, which isunsubstituted. In some embodiments, R₂₁ is -L-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₃₋₁₀aryl, which is unsubstituted and L is abond. In some embodiments, R₂₁ is -L-C₃₋₁₀aryl, which is substituted byone or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀hetaryl, which is unsubstituted and L is a bond. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₃₋₁₀cycloalkyl, which is unsubstituted and L is a bond. In someembodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀heterocyclyl, which is unsubstituted and L is a bond. In someembodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted and L is a bond. In someembodiments, R₂₁ is -L-C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₁ is -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl,which is unsubstituted. In some embodiments, R₂₁ is-L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents, where L is abond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₂₋₁₀alkenyl-C₁₋₁₀aryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstitutedand L is a bond. In some embodiments, R₂₁ is-L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₁ is-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₂₁ is -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is unsubstitutedand L is a bond. In some embodiments, R₂₁ is-L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₁ is-L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstitutedand L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₂₁ is -L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₁ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,which is unsubstituted. In some embodiments, R₂₁ is-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is unsubstituted and L is a bond.In some embodiments, R₂₁ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₂ substituents, where L is abond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted.In some embodiments, R₂₁ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which isunsubstituted. In some embodiments, R₂₁ is-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is unsubstituted and L is abond. In some embodiments, R₂₁ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which isunsubstituted. In some embodiments, R₂₁ is-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted and L is abond. In some embodiments, R₂₁ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀alkyl, which is substituted by oneor more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted and L is a bond. In someembodiments, R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀alkyl, which is substituted by oneor more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstitutedand L is a bond. In some embodiments, R₂₁ is-L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₂ substituents, where L is abond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstitutedand L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstitutedand L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstitutedand L is a bond. In some embodiments, R₂₁ is-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which isunsubstituted. In some embodiments, R₂₁ is-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted and L is abond. In some embodiments, R₂₁ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is unsubstituted.In some embodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₁ is-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is unsubstituted.In some embodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which isunsubstituted and L is a bond. In some embodiments, R₂₁ is-L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which isunsubstituted. In some embodiments, R₂₁ is-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₁ is-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is unsubstituted and L is abond. In some embodiments, R₂₁ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond.

In some embodiments of Formula I (including I-A and I-B), Formula II(including Formula II′, II-A, II-B, II-C, II-D, II-E, II-F and II-G),Formula III (including Formula III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is selected from the group consisting of -L-C₁₋₁₀heteroalkyl,-L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl, and-L-C₁₋₁₀heterocyclyl, each of which is unsubstituted or substituted byone or more independent R₁₂ substituents; and L is bond. In someembodiments, R₂₁ is -L-C₁₋₁₀hetaryl unsubstituted or substituted by oneor more independent R₁₂ substituents; and L is bond. In someembodiments, the C₁₋₁₀hetaryl of R₂₁ comprises one or more nitrogenatoms. In some embodiments, the C₁₋₁₀hetaryl of R₂₁ is selected from thegroup consisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyridazinyl. In some embodiments, the C₁₋₁₀hetaryl of R₂₁ isunsubstituted. In other embodiments, the C₁₋₁₀hetaryl or R₂₁ issubstituted with one, two, or three independent R₁₂ substituents. Insome embodiments, each R₁₂ substituent is independently selected fromthe group consisting of —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹; wherein each R₃₁ isindependently hydrogen or —C₁₋₁₀ alkyl. In further embodiments, each R₁₂substituent is independently selected from the group consisting -Me,-Et, -i-Pr, -n-Pr, OH, -OMe, -OEt, -OPr.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₁ is a substituent as shown below:

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is —OH. In some embodiments, R₂₂ is —CF₃. In some embodiments,R₂₂ is —C(O)R³¹. In some embodiments, R₂₂ is —CO₂R³¹. In someembodiments, R₂₂ is —C(═O)NR³¹. In some embodiments, R₂₂ is —S(O)₀₋₂R³¹.In some embodiments, R₂₂ is —C(═S)OR³¹. In some embodiments, R₂₂ is—C(═O)SR³¹.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀alkyl, which is unsubstituted. In some embodiments,R₂₂ is -L-C₁₋₁₀alkyl, which is substituted by one or more independentR₁₂ substituents. In some embodiments, R₂₂ is -L-C₁₋₁₀alkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl, which is substituted by one or more independent R₁₂substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₂₋₁₀alkenyl, which is unsubstituted and L is a bond. In someembodiments, R₂₂ is -L-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₂ is -L-C₂₋₁₀alkynyl, which isunsubstituted. In some embodiments, R₂₂ is -L-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₂₋₁₀alkynyl, which is unsubstituted and L is abond. In some embodiments, R₂₂ is -L-C₂₋₁₀alkynyl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀heteroalkyl, which is unsubstituted and L is a bond. In someembodiments, R₂₂ is -L-C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₂ substituents, where L is a bond

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀aryl, which is unsubstituted. In some embodiments,R₂₂ is -L-C₃₋₁₀aryl, which is substituted by one or more independent R₁₂substituents. In some embodiments, R₂₂ is -L-C₃₋₁₀aryl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is -L-C₃₋₁₀aryl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀hetaryl, which is unsubstituted and L is a bond. In someembodiments, R₂₂ is -L-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₃₋₁₀cycloalkyl, which is unsubstituted and L is a bond. In someembodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₂ is -L-C₁₋₁₀heterocyclyl, which isunsubstituted. In some embodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl, whichis substituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl, which is unsubstituted and Lis a bond. In some embodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents, where L is abond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted and L is a bond. In someembodiments, R₂₂ is -L-C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents, where L is abond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₂ is -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl,which is unsubstituted. In some embodiments, R₂₂ is-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstitutedand L is a bond. In some embodiments, R₂₂ is-L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₂₂ is -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₂ is -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,which is unsubstituted. In some embodiments, R₂₂ is-L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents, where L is abond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₂₂ is -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstitutedand L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₂₂ is-L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is substitutedby one or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted and L is a bond.In some embodiments, R₂₂ is -L-C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents, where L is abond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₂₂ is -L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted.In some embodiments, R₂₂ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which isunsubstituted. In some embodiments, R₂₂ is-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is unsubstituted and L is abond. In some embodiments, R₂₂ is -L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which isunsubstituted. In some embodiments, R₂₂ is-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted and L is abond. In some embodiments, R₂₂ is -L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀alkyl, which is substituted by oneor more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted and L is a bond. In someembodiments, R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀alkyl, which is substituted by oneor more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀hetaryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstitutedand L is a bond. In some embodiments, R₂₂ is-L-C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₂ substituents, where L is abond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstitutedand L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstitutedand L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted and L is a bond. Insome embodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₃₋₁₀aryl, which is substitutedby one or more independent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstitutedand L is a bond. In some embodiments, R₂₂ is-L-C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which isunsubstituted. In some embodiments, R₂₂ is-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted and L is abond. In some embodiments, R₂₂ is -L-C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is unsubstituted.In some embodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is unsubstituted.In some embodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is unsubstituted.In some embodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₂ substituents. In someembodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which isunsubstituted and L is a bond. In some embodiments, R₂₂ is-L-C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is substituted by one or moreindependent R₁₂ substituents, where L is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which isunsubstituted. In some embodiments, R₂₂ is-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₂ substituents. In some embodiments, R₂₂ is-L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is unsubstituted and L is abond. In some embodiments, R₂₂ is -L-C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,which is substituted by one or more independent R₁₂ substituents, whereL is a bond.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₂₂ is a substituent as shown below:

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), L is a bond. In some embodiments, L is —O—. In some embodiments,—N(R³¹)—. In some embodiments, L is —S(O)₀₋₂—. In some embodiments, L is—C(═O)—. In some embodiments, L is —C(═O)O—. In some embodiments, L is—OC(═O)—. In some embodiments, L is —C(═O)N(R³¹)—. In some embodiments,L is —N(R³¹)C(═O)—. In some embodiments, L is —NR³¹C(═O)O—. In someembodiments, L is —NR³¹C(═O)NR³²—. In some embodiments, L is—NR³¹S(O)₀₋₂—. In some embodiments, L is —S(O)₀₋₂N(R³¹)—. In someembodiments, L is —C(═S)O—. In some embodiments, L is —C(═O)S—. In someembodiments, L is —NR³¹C(═NR³²)NR³²—. In some embodiments, L is—NR³¹C(═NR³²)O—. In some embodiments, L is —NR³¹C(═NR³²)S—. In someembodiments, L is —OC(═O)O—. In some embodiments, L is —OC(═O)NR³¹—. Insome embodiments, L is —OC(═O)S—. In some embodiments, L is —SC(═O)S—.In some embodiments, L is —P(O)OR³¹O—. In some embodiments, L is—SC(═O)NR³¹—.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is hydrogen. In some embodiments, R₃ is halogen, which is F,Cl, Br, or I. In some embodiments, R₃ is —OH. In some embodiments, R₃ is—CF₃. In some embodiments, R₃ is —OCF₃. In some embodiments, R₃ is—OR³¹. In some embodiments, R₃ is —NR³¹R³². In some embodiments, R₃ is—C(O)R³¹. In some embodiments, R₃ is —CO₂R³¹. In some embodiments, R₃ is—C(═O)NR³¹. In some embodiments, R₃ is —NO₂. In some embodiments, R₃ is—CN. In some embodiments, R₃ is —S(O)₀₋₂R³¹. In some embodiments, R₃ is—SO₂NR³¹R³². In some embodiments, R₃ is —NR³¹C(═O)R³². In someembodiments, R₃ is —NR³¹C(═O)OR³². In some embodiments, R₃ is—NR³¹C(═O)NR³²R³³. In some embodiments, R₃ is —NR³¹S(O)₀₋₂R³². In someembodiments, R₃ is —C(═S)OR³¹. In some embodiments, R₃ is —C(═O)SR³¹. Insome embodiments, R₃ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₃ is—NR³¹C(═NR³²)OR³³. In some embodiments, R₃ is —NR³¹C(═NR³²)SR³³. In someembodiments, R₃ is —OC(═O)OR³³. In some embodiments, R₃ is—OC(═O)NR³¹R³². In some embodiments, R₃ is —OC(═O)SR³¹. In someembodiments, R₃ is —SC(═O)SR³¹. In some embodiments, R₃ is—P(O)OR³¹OR³². In some embodiments, R₃ is —SC(═O)NR³¹R³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkyl, which is unsubstituted. In some embodiments, R₃is —C₁₋₁₀alkyl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkenyl, which is unsubstituted. In some embodiments,R₃ is —C₂₋₁₀alkenyl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkynyl, which is unsubstituted. In some embodiments,R₃ is —C₂₋₁₀alkynyl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀aryl, which is unsubstituted. In some embodiments, R₃is —C₃₋₁₀aryl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀hetaryl, which is unsubstituted. In some embodiments,R₃ is —C₁₋₁₀hetaryl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₃ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₃ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀-aryl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₃ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is substitutedby one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is -C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₃ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₃ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₃ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₃ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₃ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₃ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₃ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is hydrogen. In some embodiments, R₃′ is halogen, which is F,Cl, Br, or I. In some embodiments, R₃′ is —OH. In some embodiments, R₃′is —CF₃. In some embodiments, R₃′ is —OCF₃. In some embodiments, R₃′ is—OR³¹. In some embodiments, R₃′ is —NR³¹R³². In some embodiments, R₃′ is—C(O)R³¹. In some embodiments, R₃′ is —CO₂R³¹. In some embodiments, R₃′is —C(═O)NR³¹. In some embodiments, R₃′ is —NO₂. In some embodiments,R₃′ is —CN. In some embodiments, R₃′ is —S(O)₀₋₂R³¹. In someembodiments, R₃′ is —SO₂NR³¹R³². In some embodiments, R₃′ is—NR³¹C(═O)R³². In some embodiments, R₃′ is —NR³¹C(═O)OR³². In someembodiments, R₃′ is —NR³¹C(═O)NR³²R³³. In some embodiments, R₃′ is—NR³¹S(O)₀₋₂R³². In some embodiments, R₃′ is —C(═S)OR³¹. In someembodiments, R₃′ is —C(═O)SR³¹. In some embodiments, R₃′ is—NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₃′ is —NR³¹C(═NR³²)OR³³. Insome embodiments, R₃′ is —NR³¹C(═NR³²)SR³³. In some embodiments, R₃′ is—OC(═O)OR³³. In some embodiments, R₃′ is —OC(═O)NR³¹R³². In someembodiments, R₃′ is —OC(═O)SR³¹. In some embodiments, R₃′ is—SC(═O)SR³¹. In some embodiments, R₃′ is —P(O)OR³¹OR³². In someembodiments, R₃′ is —SC(═O)NR³¹R³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkyl, which is unsubstituted. In some embodiments,R₃′ is —C₁₋₁₀alkyl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkenyl, which is unsubstituted. In some embodiments,R₃′ is —C₂₋₁₀alkenyl, which is substituted by one or more independentR₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkynyl, which is unsubstituted. In some embodiments,R₃′ is —C₂₋₁₀alkynyl, which is substituted by one or more independentR₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀aryl, which is unsubstituted. In some embodiments,R₃′ is —C₃₋₁₀aryl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀hetaryl, which is unsubstituted. In some embodiments,R₃′ is —C₁₋₁₀hetaryl, which is substituted by one or more independentR₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₃′ is —C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃′ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃′ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃′ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃′ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃′ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃′ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃′ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₃′ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which isunsubstituted. In some embodiments, R₃′ is—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is substituted by one or moreindependent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₃′ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₃′ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₃′ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₃′ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₃′ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃′ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₃′ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃′ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is substitutedby one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₃′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₃′ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₃′ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₃′ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₃′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₃′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₃′ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₃′ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₃′ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₃′ is —OR⁶. In some embodiments, R₃′ is —NR⁶R³⁴, whereinR⁶together with R³⁴ can optionally form a heterocyclic ring. In someembodiments, R₃′ is —S(O)₀₋₂R⁶. In some embodiments, R₃′ is —C(═O)R⁶. Insome embodiments, R₃′ is —C(═O)OR⁶. In some embodiments, R₃′ is—OC(═O)R⁶. In some embodiments, R₃′ is —C(═O)N(R³⁴)R⁶, wherein R⁶together with R³⁴ can optionally form a heterocyclic ring. In someembodiments, R₃′ is or —N(R³⁴)C(═O)R⁶, wherein R⁶ together with R³⁴ canoptionally form a heterocyclic ring;

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is hydrogen. In some embodiments, R₄ is halogen, which is F,Cl, Br, or I. In some embodiments, R₄ is —OH. In some embodiments, R₄ is—CF₃. In some embodiments, R₄ is —OCF₃. In some embodiments, R₄ is—OR³¹. In some embodiments, R₄ is —NR³¹R³². In some embodiments, R₄ is—C(O)R³¹. In some embodiments, R₄ is —CO₂R³¹. In some embodiments, R₄ is—C(═O)NR³¹. In some embodiments, R₄ is —NO₂. In some embodiments, R₄ is—CN. In some embodiments, R₄ is —S(O)₀₋₂R³¹. In some embodiments, R₄ is—SO₂NR³¹R³². In some embodiments, R₄ is —NR³¹C(═O)R³². In someembodiments, R₄ is —NR³¹C(═O)OR³². In some embodiments, R₄ is—NR³¹C(═O)NR³²R³³. In some embodiments, R₄ is —NR³¹S(O)₀₋₂R³². In someembodiments, R₄ is —C(═S)OR³¹. In some embodiments, R₄ is —C(═O)SR³¹. Insome embodiments, R₄ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₄ is—NR³¹C(═NR³²)OR³³. In some embodiments, R₄ is —NR³¹C(═NR³²)SR³³. In someembodiments, R₄ is —OC(═O)OR³³. In some embodiments, R₄ is—OC(═O)NR³¹R³². In some embodiments, R₄ is —OC(═O)SR³¹. In someembodiments, R₄ is —SC(═O)SR³¹. In some embodiments, R₄ is—P(O)OR³¹OR³². In some embodiments, R₄ is —SC(═O)NR³¹R³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkyl, which is unsubstituted. In some embodiments, R₄is —C₁₋₁₀alkyl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkenyl, which is unsubstituted. In some embodiments,R₄ is —C₂₋₁₀alkenyl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkynyl, which is unsubstituted. In some embodiments,R₄ is —C₂₋₁₀alkynyl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₃ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀aryl, which is unsubstituted. In some embodiments, R₄is —C₃₋₁₀aryl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀hetaryl, which is unsubstituted. In some embodiments,R₄ is —C₁₋₁₀hetaryl, which is substituted by one or more independent R₁₃substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀cycloalkyl, which is substituted by one or moreindependent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₄ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₄ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₄ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₄ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₄ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₄ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₄ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₄ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₄ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₄ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is substituted by one ormore independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₄ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₄ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is substituted by oneor more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₄ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₄ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₄ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is substituted byone or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₄ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₄ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₄ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₄ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₄ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which issubstituted by one or more independent R₁₃ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₅ is hydrogen. In some embodiments, R₅ is halogen, which is F,Cl, Br, or I. In some embodiments, R₅ is —C₁₋₁₀alkyl. In someembodiments, R₅ is —C₂₋₁₀alkenyl. In some embodiments, R₅ is—C₂₋₁₀alkynyl. In some embodiments, R₅ is —C₁₋₁₀heteroalkyl. In someembodiments, R₅ is —C₃₋₁₀aryl. In some embodiments, R₅ is —C₁₋₁₀hetaryl.In some embodiments, R₅ is —C₃₋₁₀cycloalkyl. In some embodiments, R₅ is—C₁₋₁₀heterocyclyl. In some embodiments, R₅ is —OH. In some embodiments,R₅ is —CF₃. In some embodiments, R₅ is —OCF₃. In some embodiments, R₅ is—OR³¹. In some embodiments, R₅ is —NR³¹R³². In some embodiments, R₅ is—C(O)R³¹. In some embodiments, R₅ is —CO₂R³¹. In some embodiments, R₅ is—C(═O)NR³¹. In some embodiments, R₅ is —NO₂. In some embodiments, R₅ is—CN. In some embodiments, R₅ is —S(O)₀₋₂R³¹. In some embodiments, R₅ is—SO₂NR³¹R³². In some embodiments, R₅ is —NR³¹C(═O)R³². In someembodiments, R₅ is —NR³¹C(═O)OR³². In some embodiments, R₅ is—NR³¹C(═O)NR³²R³³. In some embodiments, R₅ is —NR³¹S(O)₀₋₂R³². In someembodiments, R₅ is —C(═S)OR³¹. In some embodiments, R₅ is —C(═O)SR³¹. Insome embodiments, R₅ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₅ is—NR³¹C(═NR³²)OR³³. In some embodiments, R₅ is —NR³¹C(═NR³²)SR³³. In someembodiments, R₅ is —OC(═O)OR³³. In some embodiments, R₅ is—OC(═O)NR³¹R³². In some embodiments, R₅ is —OC(═O)SR³¹. In someembodiments, R₅ is —SC(═O)SR³¹. In some embodiments, R₅ is—P(O)OR³¹OR³². In some embodiments, R₅ is —SC(═O)NR³¹NR³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including IV-A, IV-B, IV-C and IV-D) and Formula V(including V-A, V-B, V-C and V-D), R₆ is —C₁₋₁₀alkyl, which isunsubstituted. In some embodiments, R₆ is —C₁₋₁₀alkyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkyl, substituted by one or more independent R₁₅ substituents. Insome embodiments, R₆ is —C₁₋₁₀alkyl, substituted by one or moreindependent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkenyl, which is unsubstituted. In some embodiments,R₆ is —C₁₋₁₀alkenyl, substituted by one or more independent R₁₄substituents. In some embodiments, R₆ is —C₁₋₁₀alkenyl, substituted byone or more independent R₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀alkenyl, substituted by one or more independent R₁₄ or R₁₅substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₂₋₁₀alkynyl, which is unsubstituted. In some embodiments,R₆ is —C₂₋₁₀alkynyl, substituted by one or more independent R₁₄substituents. In some embodiments, R₆ is —C₂₋₁₀alkynyl, substituted byone or more independent R₁₅ substituents. In some embodiments, R₆ is—C₂₋₁₀alkynyl, substituted by one or more independent R₁₄ or R₁₅substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀heteroalkyl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heteroalkyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀heteroalkyl, substitutedby one or more independent R₁₄ or R₁₅ substituents

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀aryl, which is unsubstituted. In some embodiments, R₆is —C₃₋₁₀aryl, substituted by one or more independent R₁₄ substituents.In some embodiments, R₆ is —C₃₋₁₀aryl, substituted by one or moreindependent R₁₅ substituents. In some embodiments, R₆ is —C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀hetaryl, which is unsubstituted. In some embodiments,R₆ is —C₁₋₁₀hetaryl, substituted by one or more independent R₁₄substituents. In some embodiments, R₆ is —C₁₋₁₀hetaryl, substituted byone or more independent R₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀hetaryl, substituted by one or more independent R₁₄ or R₁₅substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀cycloalkyl, substitutedby one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀heterocyclyl, substitutedby one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀alkyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkyl-C₃₋₁₀aryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl-C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, substituted by one ormore independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₆ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₂₋₁₀alkenyl-C₃₋₁₀aryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₂₋₁₀alkenyl-C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₆ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, substituted by one ormore independent R₁₄ substituents. In some embodiments, R₆ is—C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₂₋₁₀alkenyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II , II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₆ is —C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₆ is —C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₆ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₂₋₁₀alkynyl-C₃₋₁₀aryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₂₋₁₀alkynyl-C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II-A, II-B, II-C and II-D) and IIII(including III-A and III-B), R₆ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, which isunsubstituted. In some embodiments, R₆ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl,substituted by one or more independent R₁₄ substituents. In someembodiments, R₆ is —C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, substituted by one ormore independent R₁₅ substituents. In some embodiments, R₆ is—C₂₋₁₀alkynyl-C₁₋₁₀hetaryl, substituted by one or more independent R₁₄or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II-A, II-B, II-C and II-D) and IIII(including III-A and III-B), R₆ is —C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, whichis unsubstituted. In some embodiments, R₆ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₄ substituents. In some embodiments, R₆ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₂₋₁₀alkynyl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₆ is —C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₂₋₁₀alkynyl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkoxy-C₃₋₁₀aryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀alkoxy-C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkoxy-C₁₋₁₀hetaryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀alkoxy-C₁₋₁₀hetaryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, substituted by oneor more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀alkoxy-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀alkoxy-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, substituted by one ormore independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀heteroalkyl-C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₆ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₄ substituents. In someembodiments, R₆ is —C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, substituted by oneor more independent R₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₆ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₄ substituents. In someembodiments, R₆ is —C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀aryl-C₁₋₁₀alkyl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀aryl-C₁₋₁₀alkyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀aryl-C₁₋₁₀alkyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀aryl-C₂₋₁₀alkenyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀aryl-C₂₋₁₀alkenyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀aryl-C₂₋₁₀alkynyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀aryl-C₂₋₁₀alkynyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀aryl-C₃₋₁₀hetaryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀aryl-C₃₋₁₀hetaryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, substituted by one ormore independent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀aryl-C₃₋₁₀cycloalkyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀aryl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₆ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, substituted by oneor more independent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀aryl-C₁₋₁₀heterocyclyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀aryl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀hetaryl-C₁₋₁₀alkyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀hetaryl-C₁₋₁₀alkyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, substituted by one ormore independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀hetaryl-C₂₋₁₀alkenyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀hetaryl-C₂₋₁₀alkenyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, which is unsubstituted. In someembodiments, R₆ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, substituted by one ormore independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀hetaryl-C₂₋₁₀alkynyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀hetaryl-C₂₋₁₀alkynyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl, substituted by one or moreindependent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀hetaryl-C₃₋₁₀aryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀hetaryl-C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀hetaryl-C₃₋₁₀cycloalkyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀hetaryl-C₁₋₁₀heterocyclyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, substituted by one ormore independent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀cycloalkyl-C₁₋₁₀alkyl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₆ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₆ is —C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, which is unsubstituted. In someembodiments, R₆ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, substituted by one ormore independent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₃₋₁₀aryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₃₋₁₀cycloalkyl-C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₆ is —C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, which is unsubstituted.In some embodiments, R₆ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl,substituted by one or more independent R₁₄ substituents. In someembodiments, R₆ is —C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, substituted byone or more independent R₁₅ substituents. In some embodiments, R₆ is—C₃₋₁₀cycloalkyl-C₁₋₁₀heterocyclyl, substituted by one or moreindependent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₁₋₁₀alkyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkenyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₂₋₁₀alkynyl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, substituted by oneor more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₃₋₁₀aryl, substituted by one or more independent R₁₅substituents. In some embodiments, R₆ is —C₁₋₁₀heterocyclyl-C₃₋₁₀aryl,substituted by one or more independent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, which is unsubstituted. Insome embodiments, R₆ is —C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substituted byone or more independent R₁₄ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₁₋₁₀hetaryl, substituted by one or more independentR₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₆ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, which is unsubstituted.In some embodiments, R₆ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl,substituted by one or more independent R₁₄ substituents. In someembodiments, R₆ is —C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, substituted byone or more independent R₁₅ substituents. In some embodiments, R₆ is—C₁₋₁₀heterocyclyl-C₃₋₁₀cycloalkyl, substituted by one or moreindependent R₁₄ or R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₇₁ is hydrogen. In some embodiments, R₇₁ is halogen, which is F,Cl, Br, or I. In some embodiments, R₇₁ is —C₁₋₁₀alkyl. In someembodiments, R₇₁ is —C₂₋₁₀alkenyl. In some embodiments, R₇₁ is —C₂₋₁₀alkynyl. In some embodiments, R₇₁ is —C₁₋₁₀heteroalkyl. In someembodiments, R₇₁ is —C₃₋₁₀aryl. In some embodiments, R₇₁ is—C₁₋₁₀hetaryl. In some embodiments, R₇₁ is —C₃₋₁₀cycloalkyl. In someembodiments, R₇₁ is —C₁₋₁₀heterocyclyl. In some embodiments, R₇₁ is —OH.In some embodiments, R₇₁ is —CF₃. In some embodiments, R₇₁ is —OCF₃. Insome embodiments, R₇₁ is —OR³¹. In some embodiments, R₇₁ is —NR³¹R³². Insome embodiments, R₇₁ is —C(O)R³¹. In some embodiments, R₇₁ is —CO₂R³¹.In some embodiments, R₇₁ is —C(═O)NR³¹. In some embodiments, R₇₁ is—NO₂. In some embodiments, R₇₁ is —CN. In some embodiments, R₇₁ is—S(O)₀₋₂R³¹. In some embodiments, R₇₁ is —SO₂NR³¹R³². In someembodiments, R₇₁ is —NR³¹C(═O)R³². In some embodiments, R₇₁ is—NR³¹C(═O)OR³². In some embodiments, R₇₁ is —NR³¹C(═O)NR³²R³³. In someembodiments, R₇₁ is —NR³¹S(O)₀₋₂R³². In some embodiments, R₇₁ is—C(═S)OR³¹. In some embodiments, R₇₁ is —C(═O)SR³¹. In some embodiments,R₇₁ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₇₁ is—NR³¹C(═NR³²)OR³³. In some embodiments, R₇₁ is —NR³¹C(═NR³²)SR³³. Insome embodiments, R₇₁ is —OC(═O)OR³³. In some embodiments, R₇₁ is—OC(═O)NR³¹R³². In some embodiments, R₇₁ is —OC(═O)SR³¹. In someembodiments, R₇₁ is —SC(═O)SR³¹. In some embodiments, R₇₁ is—P(O)OR³¹OR³². In some embodiments, R₇₁ is —SC(═O)NR³¹NR³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₇₂ is hydrogen. In some embodiments, R₇₂ is —C₁₋₁₀alkyl. In someembodiments, R₇₂ is —C₂₋₁₀alkenyl. In some embodiments, R₇₂ is —C₂₋₁₀alkynyl. In some embodiments, R₇₂ is —C₁₋₁₀heteroalkyl. In someembodiments, R₇₂ is —C₃₋₁₀aryl. In some embodiments, R₇₂ is—C₁₋₁₀hetaryl. In some embodiments, R₇₂ is —C₃₋₁₀cycloalkyl. In someembodiments, R₇₂ is —C₁₋₁₀heterocyclyl. In some embodiments, R₇₂ is —OH.In some embodiments, R₇₂ is —CF₃. In some embodiments, R₇₂ is —C(O)R³¹.In some embodiments, R₇₂ is —CO₂R³¹. In some embodiments, R₇₂ is—C(═O)NR³¹. In some embodiments, R₇₂ is —S(O)₀₋₂R³¹. In someembodiments, R₇₂ is —C(═S)OR³¹. In some embodiments, R₇₂ is —C(═O)SR³¹.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₈₁ is hydrogen. In some embodiments, R₈₁ is halogen, which is F,Cl, Br, or I. In some embodiments, R₈₁ is —C₁₋₁₀alkyl. In someembodiments, R₈₁ is —C₂₋₁₀alkenyl. In some embodiments, R₈₁ is—C₂₋₁₀alkynyl. In some embodiments, R₈₁ is —C₁₋₁₀heteroalkyl. In someembodiments, R₈₁ is —C₃₋₁₀aryl. In some embodiments, R₈₁ is—C₁₋₁₀hetaryl. In some embodiments, R₈₁ is —C₃₋₁₀cycloalkyl. In someembodiments, R₈₁ is —C₁₋₁₀heterocyclyl. In some embodiments, R₈₁ is —OH.In some embodiments, R₈₁ is —CF₃. In some embodiments, R₈₁ is —OCF₃. Insome embodiments, R₈₁ is —OR³¹. In some embodiments, R₈₁ is —NR³¹R³². Insome embodiments, R₈₁ is —C(O)R³¹. In some embodiments, R₁ is —CO₂R³¹.In some embodiments, R₈₁ is —C(═O)NR³¹. In some embodiments, R₈₁ is—NO₂. In some embodiments, R₈₁ is —CN. In some embodiments, R₈₁ is—S(O)₀₋₂R³¹. In some embodiments, R₈₁ is —SO₂NR³¹R³². In someembodiments, R₈₁ is —NR³¹C(═O)R³². In some embodiments, R₈₁ is—NR³¹C(═O)OR³². In some embodiments, R₈₁ is —NR³¹C(═O)NR³²R³³. In someembodiments, R₈₁ is —NR³¹S(O)₀₋₂R³². In some embodiments, R₈₁ is—C(═S)OR³¹. In some embodiments, R₈₁ is —C(═O)SR³¹. In some embodiments,R₈ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₈₁ is—NR³¹C(═NR³²)OR³³. In some embodiments, R₈₁ is —NR³¹C(═NR³²)SR³³. Insome embodiments, R₈₁ is —OC(═O)OR³³. In some embodiments, R₈₁ is—OC(═O)NR³¹R³². In some embodiments, R₈₁ is —OC(═O)SR³¹. In someembodiments, R₈₁ is —SC(═O)SR³¹. In some embodiments, R₈₁ is—P(O)OR³¹R³². In some embodiments, R₈₁ is —SC(═O)NR³¹NR³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₈₂ is hydrogen. In some embodiments, R₈₂ is —C₁₋₁₀alkyl. In someembodiments, R₈₂ is —C₂₋₁₀alkenyl. In some embodiments, R₈₂ is —C₂₋₁₀alkynyl. In some embodiments, R₈₂ is —C₁₋₁₀heteroalkyl. In someembodiments, R₈₂ is —C₃₋₁₀aryl. In some embodiments, R₈₂ is—C₁₋₁₀hetaryl. In some embodiments, R₈₂ is —C₃₋₁₀cycloalkyl. In someembodiments, R₈₂ is —C₁₋₁₀heterocyclyl. In some embodiments, R₈₂ is —OH.In some embodiments, R₈₂ is —CF₃. In some embodiments, R₈₂ is —C(O)R³¹.In some embodiments, R₈₂ is —CO₂R³¹. In some embodiments, R₈₂ is—C(═O)NR³¹. In some embodiments, R₈₂ is —S(O)₀₋₂R³¹. In someembodiments, R₈₂ is —C(═S)OR³¹. In some embodiments, R₈₂ is —C(═O)SR³¹.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₉₁ is hydrogen. In some embodiments, R₉₁ is halogen, which is F,—Cl, Br, or I. In some embodiments, R₉₁ is —C₁₋₁₀alkyl. In someembodiments, R₉₁ is —C₂₋₁₀alkenyl. In some embodiments, R₉₁ is —C₂₋₁₀alkynyl. In some embodiments, R₉₁ is —C₁₋₁₀heteroalkyl. In someembodiments, R₉₁ is —C₃₋₁₀aryl. In some embodiments, R₉₁ is—C₁₋₁₀hetaryl. In some embodiments, R₉₁ is —C₃₋₁₀cycloalkyl. In someembodiments, R₉₁ is —C₁₋₁₀heterocyclyl. In some embodiments, R₉₁ is —OH.In some embodiments, R₉₁ is —CF₃. In some embodiments, R₉₁ is —OCF₃. Insome embodiments, R₉₁ is —OR³¹. In some embodiments, R₉₁ is —NR³¹R³². Insome embodiments, R₉₁ is —C(O)R³¹. In some embodiments, R₉₁ is —CO₂R³¹.In some embodiments, R₉₁ is —C(═O)NR³¹. In some embodiments, R₉₁ is—NO₂. In some embodiments, R₉₁ is —CN. In some embodiments, R₉₁ is—S(O)₀₋₂R³¹. In some embodiments, R₉₁ is —SO₂NR³¹R³². In someembodiments, R₉₁ is —NR³¹C(═O)R³². In some embodiments, R₉₁ is—NR³¹C(═O)OR³². In some embodiments, R₉₁ is —NR³¹C(═O)NR³²R³³. In someembodiments, R₉₁ is —NR³¹S(O)₀₋₂R³². In some embodiments, R₉₁ is—C(═S)OR³¹. In some embodiments, R₉₁ is —C(═O)SR³¹. In some embodiments,R₉ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₉₁ is—NR³¹C(═NR³²)OR³³. In some embodiments, R₉₁ is —NR³¹C(═NR³²)SR³³. Insome embodiments, R₉₁ is —OC(═O)OR³³. In some embodiments, R₉₁ is—OC(═O)NR³¹R³². In some embodiments, R₉₁ is —OC(═O)SR³¹. In someembodiments, R₉₁ is —SC(═O)SR³¹. In some embodiments, R₉₁ is—P(O)OR³¹OR³². In some embodiments, R₉₁ is —SC(═O)NR³¹NR³²;

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₉₂ is hydrogen. In some embodiments, R₉₂ is —C₁₋₁₀alkyl. In someembodiments, R₉₂ is —C₂₋₁₀alkenyl. In some embodiments, R₉₂ is-C₂₋₁₀alkynyl. In some embodiments, R₉₂ is —C₁₋₁₀heteroalkyl. In someembodiments, R₉₂ is —C₃₋₁₀aryl. In some embodiments, R₉₂ is—C₁₋₁₀hetaryl. In some embodiments, R₉₂ is —C₃₋₁₀cycloalkyl. In someembodiments, R₉₂ is —C₁₋₁₀heterocyclyl. In some embodiments, R₉₂ is —OH.In some embodiments, R₉₂ is —CF₃. In some embodiments, R₉₂ is —C(O)R³¹.In some embodiments, R₉₂ is —CO₂R³¹. In some embodiments, R₉₂ is—C(═O)NR³¹. In some embodiments, R₉₂ is —S(O)₀₋₂R³¹. In someembodiments, R₉₂ is —C(═S)OR³¹. In some embodiments, R₉₂ is —C(═O)SR³¹.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₀ is —C₁₋₁₀alkyl, which is unsubstituted. In some embodiments,R₁₀ is —C₁₋₁₀alkyl, which is substituted by one or more independent R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₀ is —C₂₋₁₀alkenyl, which is unsubstituted. In some embodiments,R₁₀ is —C₂₋₁₀alkenyl, which is substituted by one or more independentR₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₀ is —C₂₋₁₀alkynyl, which is unsubstituted. In some embodiments,R₁₀ is —C₂₋₁₀alkynyl, which is substituted by one or more independentR₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₀ is —C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₁₀ is —C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₀ is —C₃₋₁₀aryl, which is unsubstituted. In some embodiments,R₁₀ is —C₃₋₁₀aryl, which is substituted by one or more independent R₁₁substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₀ is —C₁₋₁₀hetaryl, which is unsubstituted. In some embodiments,R₁₀ is —C₁₋₁₀hetaryl, which is substituted by one or more independentR₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₀ is —C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₁₀ is —C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₀ is —C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₁₀ is —C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₁ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₄ is —C₁₋₁₀alkyl, which is unsubstituted. In some embodiments,R₁₄ is —C₁₋₁₀alkyl, which is substituted by one or more independent R₁₅substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₄ is —C₂₋₁₀alkenyl, which is unsubstituted. In some embodiments,R₁₄ is —C₂₋₁₀alkenyl, which is substituted by one or more independentR₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₄ is —C₂₋₁₀alkynyl, which is unsubstituted. In some embodiments,R₁₄ is —C₂₋₁₀alkynyl, which is substituted by one or more independentR₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₄ is —C₁₋₁₀heteroalkyl, which is unsubstituted. In someembodiments, R₁₄ is —C₁₋₁₀heteroalkyl, which is substituted by one ormore independent R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₄ is —C₃₋₁₀aryl, which is unsubstituted. In some embodiments,R₁₄ is —C₃₋₁₀aryl, which is substituted by one or more independent R₁₅substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₄ is —C₁₋₁₀hetaryl, which is unsubstituted. In some embodiments,R₁₄ is —C₁₋₁₀hetaryl, which is substituted by one or more independentR₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₄ is —C₃₋₁₀cycloalkyl, which is unsubstituted. In someembodiments, R₁₄ is —C₃₋₁₀cycloalkyl, which is substituted by one ormore independent R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₄ is —C₁₋₁₀heterocyclyl, which is unsubstituted. In someembodiments, R₁₄ is —C₁₋₁₀heterocyclyl, which is substituted by one ormore independent R₁₅ substituents.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₁ is hydrogen. In some embodiments, R₁ is halogen, which is F,Cl, Br, or I. In some embodiments, R₁₁ is —C₁₋₁₀alkyl. In someembodiments, R₁ is —C₂₋₁₀alkenyl. In some embodiments, R₁ is —C₂₋₁₀alkynyl. In some embodiments, R₁ is —C₁₋₁₀heteroalkyl. In someembodiments, R₁₁ is —C₃₋₁₀aryl. In some embodiments, R₁ is—C₁₋₁₀hetaryl. In some embodiments, R₁₁ is —C₃₋₁₀cycloalkyl. In someembodiments, R₁₁ is —C₁₋₁₀heterocyclyl. In some embodiments, R₁₁ is —OH.In some embodiments, R₁ is —CF₃. In some embodiments, R₁ is —OCF₃. Insome embodiments, R₁ is —OR³¹. In some embodiments, R₁ is —NR³¹R³². Insome embodiments, R₁ is —C(O)R³¹. In some embodiments, R₁ is —CO₂R³¹. Insome embodiments, R₁ is —C(═O)NR³¹. In some embodiments, R₁ is —NO₂. Insome embodiments, R₁ is —CN. In some embodiments, R₁ is —S(O)₀₋₂R³¹. Insome embodiments, R₁ is —SO₂NR³¹R³². In some embodiments, R₁ is—NR³¹C(═O)R³². In some embodiments, R₁ is —NR³¹C(═O)OR³². In someembodiments, R₁ is —NR³¹C(═O)NR³²R³³. In some embodiments, R₁₁ is—NR³¹S(O)₀₋₂R³². In some embodiments, R₁ is —C(═S)OR³¹. In someembodiments, R₁ is —C(═O)SR³¹. In some embodiments, R₁₁ is—NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₁₁ is —NR³¹C(═NR³²)OR³³. Insome embodiments, R₁ is —NR³¹C(═NR³²)SR³³. In some embodiments, R₁₁ is—OC(═O)OR³³. In some embodiments, R₁ is —OC(═O)NR³¹R³². In someembodiments, R₁₁ is —OC(═O)SR³¹. In some embodiments, R₁₁ is—SC(═O)SR³¹. In some embodiments, R₁₁ is —P(O)OR³¹OR³². In someembodiments, R₁₁ is or —SC(═O)NR³¹NR³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₂ is hydrogen. In some embodiments, R₁₂ is halogen, which is F,Cl, Br, or I. In some embodiments, R₁₂ is —C₁₋₁₀alkyl. In someembodiments, R₁₂ is —C₂₋₁₀alkenyl. In some embodiments, R₁₂ is—C₂₋₁₀alkynyl. In some embodiments, R₁₂ is —C₁₋₁₀heteroalkyl. In someembodiments, R₁₂ is —C₃₋₁₀aryl. In some embodiments, R₁₂ is—C₁₋₁₀hetaryl. In some embodiments, R₁₂ is —C₃₋₁₀cycloalkyl. In someembodiments, R₁₂ is —C₁₋₁₀heterocyclyl. In some embodiments, R₁₂ is —OH.In some embodiments, R₁₂ is —CF₃. In some embodiments, R₁₂ is —OCF₃. Insome embodiments, R₁₂ is —OR³¹. In some embodiments, R₁₂ is —NR³¹R³². Insome embodiments, R₁₂ is —C(O)R³¹. In some embodiments, R₁₂ is —CO₂R³¹.In some embodiments, R₁₂ is —C(═O)NR³¹. In some embodiments, R₁₂ is—NO₂. In some embodiments, R₁₂ is —CN. In some embodiments, R₁₂ is—S(O)₀₋₂R³¹. In some embodiments, R₁₂ is —SO₂NR³¹R³². In someembodiments, R₁₂ is —NR³¹C(═O)R³². In some embodiments, R₁₂ is—NR³¹C(═O)OR³². In some embodiments, R₁₂ is —NR³¹C(═O)NR³²R³³. In someembodiments, R₁₂ is —NR³¹S(O)₀₋₂R³². In some embodiments, R₁₂ is—C(═S)OR³¹. In some embodiments, R₁₂ is —C(═O)SR³¹. In some embodiments,R₁₂ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments, R₁₂ is—NR³¹C(═NR³²)OR³³. In some embodiments, R₁₂ is —NR³¹C(═NR³²)SR³³. Insome embodiments, R₁₂ is —OC(═O)OR³³. In some embodiments, R₁₂ is—OC(═O)NR³¹R³². In some embodiments, R₁₂ is —OC(═O)SR³¹. In someembodiments, R₁₂ is —SC(═O)SR³¹. In some embodiments, R₁₂ is—P(O)OR³¹R³². In some embodiments, R₁₂ is —SC(═O)NR³¹NR³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₃ is hydrogen. In some embodiments, R₁₃ is halogen, which is F,Cl, Br, or I. In some embodiments, R₁₃ is —C₁₋₁₀alkyl. In someembodiments, R₁₃ is —C₂₋₁₀alkenyl. In some embodiments, R₁₃ is—C₂₋₁₀alkynyl. In some embodiments, R₁₃ is —C₁₋₁₀heteroalkyl. In someembodiments, R₁₃ is —C₃₋₁₀aryl. In some embodiments, R₁₃ is—C₁₋₁₀hetaryl. In some embodiments, R₁₃ is —C₃₋₁₀cycloalkyl. In someembodiments, R₁₃ is —C₁₋₁₀heterocyclyl. In some embodiments, R₁₃ is —OH.In some embodiments, R₁₃ is —CF₃. In some embodiments, R₁₃ is —OCF₃. Insome embodiments, R₁₃ is —OR³¹. In some embodiments, R₁₃ is —NR³¹R³². Insome embodiments, R₁₃ is —C(O)R³¹. In some embodiments, R₁₃ is —CO₂R³¹.In some embodiments, R₁₃ is —C(═O)NR³¹. In some embodiments, R₁₃ is—NO₂. In some embodiments, R₁₃ is —CN, —S(O)₀₋₂R³¹. In some embodiments,R₁₃ is —SO₂NR³¹R³². In some embodiments, R₁₃ is —NR³¹C(═O)R³². In someembodiments, R₁₃ is —NR³¹C(═O)OR³². In some embodiments, R₁₃ is—NR³¹C(═O)NR³²R³³. In some embodiments, R₁₃ is —NR³¹S(O)₀₋₂R³². In someembodiments, R₁₃ is —C(═S)OR³¹. In some embodiments, R₁₃ is —C(═O)SR³¹.In some embodiments, R₁₃ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments,R₁₃ is —NR³¹C(═NR³²)OR³³. In some embodiments, R₁₃ is —NR³¹C(═NR³²)SR³³.In some embodiments, R₁₃ is —OC(═O)OR³³. In some embodiments, R₁₃ is—OC(═O)NR³¹R³². In some embodiments, R₁₃ is —OC(═O)SR³¹. In someembodiments, R₁₃ is —SC(═O)SR³¹. In some embodiments, R₁₃ is—P(O)OR³¹OR³². In some embodiments, R₁₃ is —SC(═O)NR³¹NR³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R₁₅ is hydrogen. In some embodiments, R₁₅ is halogen, which is F,Cl, Br, or I. In some embodiments, R₁₅ is —C₁₋₁₀alkyl. In someembodiments, R₁₅ is —C₂₋₁₀alkenyl. In some embodiments, R₁₅ is—C₂₋₁₀alkynyl. In some embodiments, R₁₅ is —C₁₋₁₀heteroalkyl. In someembodiments, R₁₅ is —C₃₋₁₀aryl. In some embodiments, R₁₅ is—C₁₋₁₀hetaryl. In some embodiments, R₁₅ is —C₃₋₁₀cycloalkyl. In someembodiments, R₁₅ is —C₁₋₁₀heterocyclyl. In some embodiments, R₁₅ is —OH.In some embodiments, R₁₅ is —CF₃. In some embodiments, R₁₅ is —OCF₃. Insome embodiments, R₁₅ is —OR³¹. In some embodiments, R₁₅ is —NR³¹R³². Insome embodiments, R₁₅ is —C(O)R³¹. In some embodiments, R₁₅ is —CO₂R³¹.In some embodiments, R₁₅ is —C(═O)NR³¹. In some embodiments, R₁₅ is—NO₂. In some embodiments, R₁₅ is —CN, —S(O)₀₋₂R³¹. In some embodiments,R₁₅ is —SO₂NR³¹R³². In some embodiments, R₁₅ is —NR³¹C(═O)R³². In someembodiments, R₁₅ is —NR³¹C(═O)OR³². In some embodiments, R₁₅ is—NR³¹C(═O)NR³²R³³. In some embodiments, R₁₅ is —NR³¹S(O)₀₋₂R³². In someembodiments, R₁₅ is —C(═S)OR³¹. In some embodiments, R₁₅ is —C(═O)SR³¹.In some embodiments, R₁₅ is —NR³¹C(═NR³²)NR³²R³³. In some embodiments,R₁₅ is —NR³¹C(═NR³²)OR³³. In some embodiments, R₁₅ is —NR³¹C(═NR³²)SR³³.In some embodiments, R₁₅ is —OC(═O)OR³³. In some embodiments, R₁₅ is—OC(═O)NR³¹R³². In some embodiments, R₁₅ is —OC(═O)SR³¹. In someembodiments, R₁₅ is —SC(═O)SR³¹. In some embodiments, R₁₅ is—P(O)OR³¹OR³². In some embodiments, R₁₅ is —SC(═O)NR³¹NR³².

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R³¹ is hydrogen. In some embodiments, R³¹ is halogen, which is F,Cl, Br, or I. In some embodiments, R³¹ is —C₁₋₁₀alkyl. In someembodiments, R³¹ is —C₂₋₁₀alkenyl. In some embodiments, R³¹ is—C₂₋₁₀alkynyl. In some embodiments, R³¹ is —C₁₋₁₀heteroalkyl. In someembodiments, R³¹ is —C₃₋₁₀aryl. In some embodiments, R³¹ is—C₁₋₁₀hetaryl. In some embodiments, R³¹ is —C₃₋₁₀cycloalkyl. In someembodiments, R³ is —C₁₋₁₀heterocyclyl.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R³² is hydrogen. In some embodiments, R³² is halogen, which is F,Cl, Br, or I. In some embodiments, R³² is —C₁₋₁₀alkyl. In someembodiments, R³² is —C₂₋₁₀alkenyl. In some embodiments, R³² is —C₂₋₁₀alkynyl. In some embodiments, R³² is —C₁₋₁₀heteroalkyl. In someembodiments, R³² is —C₃₋₁₀aryl. In some embodiments, R³² is—C₁₋₁₀hetaryl. In some embodiments, R³² is —C₃₋₁₀cycloalkyl. In someembodiments, R³² is —C₁₋₁₀heterocyclyl.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R³³ is hydrogen. In some embodiments, R³³ is halogen, which is F,Cl, Br, or I. In some embodiments, R³³ is —C₁₋₁₀alkyl. In someembodiments, R³³ is —C₂₋₁₀alkenyl. In some embodiments, R³³ is —C₂₋₁₀alkynyl. In some embodiments, R³³ is —C₁₋₁₀heteroalkyl. In someembodiments, R³³ is —C₃₋₁₀aryl. In some embodiments, R³³ is—C₁₋₁₀hetaryl. In some embodiments, R³³ is —C₃₋₁₀cycloalkyl. In someembodiments, R³³ is —C₁₋₁₀heterocyclyl.

In various embodiments of compounds of Formula I (including I-A andI-B), Formula II (including II′, II-A, II-B, II-C, II-D, II-E, II-F andII-G), Formula III (including III-A and III-B), Formula IV (includingIV-A, IV-B, IV-C and IV-D) and Formula V (including V-A, V-B, V-C andV-D), R³⁴ is hydrogen. In some embodiments, R³⁴ is halogen, which is F,Cl, Br, or I. In some embodiments, R³⁴ is —C₁₋₁₀alkyl. In someembodiments, R³⁴ is —C₂₋₁₀alkenyl. In some embodiments, R³⁴ is —C₂₋₁₀alkynyl. In some embodiments, R³⁴ is —C₁₋₁₀heteroalkyl. In someembodiments, R³⁴ is —C₃₋₁₀aryl. In some embodiments, R³⁴ is—C₁₋₁₀hetaryl. In some embodiments, R³⁴ is —C₃₋₁₀cycloalkyl. In someembodiments, R³⁴ is —C₁₋₁₀heterocyclyl.

B. Reaction Schemes

The compounds disclosed herein may be prepared by the routes describedbelow. Materials used herein are either commercially available orprepared by synthetic methods generally known in the art. These schemesare not limited to the compounds listed or by any particularsubstituents employed for illustrative purposes. Numbering does notnecessarily correspond to that of claims or other tables.

In some embodiments, compounds are synthesized by coupling an R²¹ moietyonto an N-protected indazole A-3 via a coupling reaction (e.g. Suzukireaction) to produce a compound of Formula A-4. The intermediate A-4 istreated with an N-bromosuccinimide (NBS) reagent to install a bromidegroup at the allylic position as in A-5, which is then reacted with anamino group to introduce the R1 group and produce a compound of FormulaA-6. Reduction of the nitro group with a zinc catalyst under acidicconditions yields the bis-amino heteroaromatic compound A-7, which isthen condensed with carbonyl diimidazole (CDI) to produce a tricycliccompound of Formula A-8. Deprotection of the protecting groups underacidic conditions affords compound A-9.

In other embodiments, the R²¹ moiety is coupled onto an N-protectedindazole B-5 via a first coupling reaction (e.g. Suzuki reaction) toproduce a compound of Formula B-6. A vinyl group is subsequentlyintroduced to B-6 via a second coupling reaction (e.g. Stille reaction)as in B-7, which is then treated with osmium tetroxide and sodiumperiodate to produce the aldehyde B-8. The intermediate B-8 is thenreacted with an amino group to introduce the R1 group, followed byreduction with sodium borohydride to afford a compound of formula B-8.The protecting groups are removed under acidic conditions to afford thebis-amino indazole B-10, which is condensed with carbonyl diimidazole(CDI) to produce a tricyclic compound of Formula B-11.

In yet other embodiments, a vinyl group can be introduced to theN-protected indazole C-1 via a first coupling reaction (e.g. Stillereaction) as in C-2, which is then treated with osmium tetroxide andsodium periodate to produce the aldehyde C-3. The intermediate C-3 isreacted with an amino group to introduce the R1 moiety as in C-4.Reduction of the nitro group with a zinc catalyst under acidicconditions yields the bis-amino heteroaromatic compound C-5, which isthen condensed with carbonyl diimidazole (CDI) to produce a tricycliccompound of Formula C-6. The compound C-6 is deprotected under acidicconditions and treated with N-iodosuccinimide (NIS) to produce theiodo-indazole C-7. After installing the trityl protecting groups underbasic conditions as in C-8, the R²¹ group was introduced via a secondcoupling reaction (e.g. Stille reaction) to produce the N-protectedtricyclic compound C-9. Removal of the protecting groups under acidicconditions provides compounds of Formula C-11.

In some embodiments, N-protected indazole A-3 is brominated using NBS toprovide dibromide D-1, which is then reacted with an amino group tointroduce the R1 moiety to yield intermediate D-2. Reduction of thenitro group with a zinc catalyst under acidic conditions yields thebis-amino heteroaromatic compound D-3, which is then condensed withcarbonyl diimidazole (CDI) to produce a tricyclic compound of FormulaD-4. The R²¹ group is introduced via a coupling reaction (e.g. Suzukireaction) to produce the N-protected tricyclic compound D-5. Removal ofthe protecting groups under acidic conditions provides compounds ofFormula D-6.

In other embodiments, intermediate B-4 is reacted with an acyl chlorideto form amide E-1. The R²¹ group is installed via a first couplingreaction (e.g. Suzuki reaction) to afford in intermediate E-2. A vinylgroup can be introduced via a second coupling reaction (e.g. Stillereaction) as in E-3, which is then treated with osmium tetroxide andsodium periodate to produce the aldehyde E-4. The tricyclic compound E-5is produced via an intramolecular aldol condensation under basicconditions. Removal of the protecting groups under acidic conditionsyields compounds of Formula E-6.

Alternatively, intermediate B-8 can be deacetylated to form analine F-1.Treatment of F-1 with an acyl chloride in the presence of TEA furnishesthe corresponding amide E-4. The tricyclic compound E-5 is produced viaan intramolecular aldol condensation under basic conditions. Removal ofthe protecting groups under acidic conditions yields compounds ofFormula E-6.

In some embodiments, dibromo compound G-1 can be treated with potassiumacetate in DMF to form acetate G-2. The nitro group can be reduced inthe presence of sodium thiosulfate and subsequent hydrolysis of theester with lithium hydroxide can provide amino alcohol G-4. Oxidation ofthe benzylic alcohol to the aldehyde furnishes G-5. Acylation with anacyl chloride can form the corresponding amide G-6. The tricycliccompound G-7 can be formed via intramolecular aldol condensation. TheR21 group can be introduced via coupling with the aryl bromide G-7 (e.g.Suzuki coupling). Removal of the protecting groups under acidicconditions yields compounds of Formula G-9.

In some embodiments, bicyclic compound H-1 can be treated with NBS andAIBN to provide the corresponding bromide H-2. Treatment with an aminecan form the corresponding benzylic amine H-3. Subsequent reduction ofthe nitro arene furnishes the aniline H-4. The tricyclic compound isformed via the addition of CDI. The R²¹ group can be introduced via acoupling reaction with a boronic acid (e.g. Suzuki coupling). Removal ofthe protecting group via hydrogenation and treatment with Boc anhydridecan furnish the Boc-protected amine H-7. Removal of the Boc group underacid conditions and reductive amination with an aldehyde can form thesubstituted amine H-9.

In some embodiments, bromide H-2 is coupled to an amine to form thecorresponding benzyl amine I-1. Treatment with ethyl 2-chloroacetate inthe presence of base can produce 1-2. Reduction of the aryl nitro groupin with Zn in acetic acid leads to tricyclic compound 1-3. The R²¹ groupcan be introduced via a coupling reaction with a boronic acid (e.g.Suzuki coupling) to give the product 1-4. Removal of the protectinggroup under acidic conditions can give the product 1-5.

In some embodiments, aryl olefin C-2 can be hydroborated to form thelinear alcohol J-1. Oxidation of the alcohol to J-2 can furnish thecarboxylic acid. The acid can be coupled to an amine to form amide J-3thereby introducing the R1 group via an amide bond-forming reaction.Reduction of the amide via borane can provide the amine J-4, and furtherreduction of the nitro group with zinc in acetic acid can provideanaline J-5. The tricyclic compound J-6 can be formed via addition ofCDI. Deprotection under acidic conditions and subsequent iodinationleads to aryl iodide J-8. Protection with a Boc group give intermediateJ-9 which can be coupled via a coupling reaction (i.e. Suzuki reaction)to introduce the R21 group. Removal of the Boc group gives product J-10.

In some embodiments, aryl bromide B-1 is coupled to an amine to formK-2. Reduction of the aryl nitro group furnishes aniline K-3. Tricycliccompound K-4 is formed via addition of triphosgene. The protecting groupis removed under acidic conditions to form compound K-5, which isiodinated with NIS to furnish aryl iodide K-6. Protection of thecompound with a Boc group give K-7. Coupling of K-7 via a couplingreaction can introduce the R21 group (i.e. Suzuki coupling) to furnishcompound K-8.

In some embodiments, aldehyde G-5 is olefinated (i.e. HWE reaction) tofurnish ester L-1. Treatment with base such as DBU provides tricycliccompound L-2. The R²¹ group can be introduced via a coupling reactionwith a boronic acid (e.g. Suzuki coupling) to form L-3. Brominationselective furnishes L-4 which can be coupled to form L-5. Reduction ofthe olefin and removal of the benzyl group furnishes L-6. Deprotectionunder acidic conditions and subsequent reductive amination can provideL-8.

In some embodiments, aldehyde M-1 is oxidized to the acid M-2 with Jonesreagent. Cleavage of the acetate group is achieved under acidicconditions to form M-3. Coupling to an amine (i.e. amide bond formingreaction) is used to introduce the R1 group thereby forming M-4. Thetricyclic compound M-5 is formed by addition of CDI.

In other embodiments, compound N-1 is brominated with NIS selectively toform N-1. Coupling to a vinyl boronic acid or boronic ester can be usedto furnish N-3 and introduce an R¹⁰ group. Hydroboration and oxidationof the olefin can furnish alcohol N-4. Removal of the protecting groupunder acid conditions yields N-5.

In some embodiments, compound O-1 can be selectively coupled at thepyrazole nitrogen to form O-2. Removal of the tert-butyl groups underacidic conditions can form O-3.

In some embodiments, a compound of the structure P-1 can be oxidized toP-2, for example, in the presence of potassium permanganate.

Some exemplary R¹ moieties that can be incorporated via any of SchemesA-P include but are not limited to:

Additional exemplary R¹ moieties that can be incorporated via any ofSchemes A-P include but are not limited to:

Some exemplary R²¹ and/or R²² moieties that can be incorporated via anyof Schemes A-P include but are not limited to:

Some exemplary compounds that can be synthesized by any of Schemes A-Pinclude but are not limited to those disclose in Table 1 (see Examples).

C. Methods of Using the Compositions Disclosed Herein

The present invention provides a method of inhibiting the activity ofone or more kinases of ERK family (including ERK1 and ERK2) ERK in acell comprising contacting the cell with an effective amount of one ormore compounds disclosed herein. Inhibition of kinase activity can beassessed and demonstrated by a wide variety of ways known in the art.Non-limiting examples include (a) immunoblotting and immunoprecipitationwith antibodies such as anti-phosphotyrosine, anti-phosphoserine oranti-phosphothreonine antibodies that recognize phosphorylated proteins;(b) using antibodies that specifically recognize a particularphosphorylated form of a kinase substrate (e.g. anti-phospho ERK); (c)cell proliferation assays, such as but not limited to tritiatedthymidine uptake assays, BrdU (5′-bromo-2′-deoxyuridine) uptake (kitmarketed by Calibochem), MTS uptake (kit marketed by Promega), MTTuptake (kit marketed by Cayman Chemical), CyQUANT dye uptake (marketedby Invitrogen).

Selective PI3Kα inhibition may also be determined by expression levelsof the PI3Kα genes, its downstream signaling genes (for example byRT-PCR), or expression levels of the proteins (for example byimmunocytochemistry, immunohistochemistry, Western blots) as compared toother PI3-kinases or protein kinases.

Kits and commercially available assays can be utilized for determiningone or more of the above.

In some embodiments, the practice of a subject method involves acontacting step taking place in vitro. In other embodiments, thecontacting step takes place in vivo.

Any of the compounds shown above may show a biological activity in anERK inhibition assay of between about 0.5 nM and 25 μM (IC₀).

In some embodiments, one or more compounds of the invention may bindspecifically to an ERK (MAPK) kinase or a protein kinase selected fromthe group consisting of Ras, Raf, JNK, ErbB-1 (EGFR), Her2 (ErbB-2), Her3 (ErbB-3), Her 4 (ErbB-4), MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K3 (MEK3),MAP2K4 (MEK4). MAP2K5 (MEK5), MAP2K6 (MEK6), MAP2K7 (MEK7), CDK1, CDK2,CDK3, CDK4, CDK5, CDK6, CDK7T, CDK8, CDK9, CDK11 and any other proteinkinases listed in the appended tables and figures, as well as anyfunctional mutants thereof.

In some embodiments, the IC50 of a compound of the invention for ERK 1and/or ERK2 is less than about 1 μM, less than about 100 nM, less thanabout 50 nM, less than about 10 nM, less than 1 nM or even less thanabout 0.5 nM. In some embodiments, the IC50 of a compound of theinvention for ERK is less than about 1 μM, less than about 100 nM, lessthan about 50 nM, less than about 10 nM, less than 1 nM or even lessthan about 0.5 nM. In some other embodiments, one or more compounds ofthe invention exhibit dual binding specificity and are capable ofinhibiting an ERK kinase (e.g., ERK-1 kinase, ERK-2 kinase, etc.) aswell as a protein kinase (e.g., Ras, Raf, Her-2, MEK1, etc.) with anIC50 value less than about 1 μM, less than about 100 nM, less than about50 nM, less than about 10 nM, less than 1 nM or even less than about 0.5nM. In some embodiments, one or more compounds of the invention may becapable of inhibiting kinases involved in the Ras-Raf-MEK-ERK pathwayincluding, for example, Ras, Raf, JNK, ErbB-1 (EGFR), Her2 (ErbB-2),Her3 (ErbB-3), Her4 (ErbB-4). MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K3(MEK3), MAP2K4 (MEK4), MAP2K5 (MEK5), MAP2K6 (MEK6). MAP2K7 (MEK7),CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK11, andfunctional mutants thereof. In some embodiments, the kinase is Ras, Raf.JNK, ErbB-1 (EGFR), Her2 (ErbB-2), MAP2K1 (MEK1), CDK1, CDK2, CDK3, CDK4CDK5, CDK6, or any other kinases listed in the Tables herein.

In still another embodiment, the compounds of the invention includingbut not limited to those shown in Table 1 selectively inhibit ERK 1and/or ERK2 activity relative to one or more protein kinases includingbut not limited to serine/threonine kinase such as DNA-PK and mTor. Suchselective inhibition can be evidenced by, e.g., the IC₅₀ value of thecompound of the invention that can be ½, ⅓^(rd), ¼^(th), ⅕^(th),1/7^(th), 1/10^(th), 1/20^(th), 1/25^(th), 1/50^(th), 1/100^(th),1/200^(th), 1/300^(th), 1/400^(th), 1/500^(th), 1/1000^(th), 1/2000^(th)or less as compared to that of a reference protein kinase. In someinstances, the compounds of the invention including but not limited tothose shown in Table 1 lack substantial cross-reactivity with at leastabout 100, 200, 300, or more protein kinases other than ERK1 or ERK2.The lack of substantial cross-reactivity with other non-ERK proteinkinases can be evidenced by, e.g., at least 50%, 60%, 70%, 80%, 90% orhigher kinase activity retained when the compound of the invention isapplied to the protein kinase at a concentration of 1 μM, 5 μM, 10 μM orhigher.

In some embodiments, one or more compounds of the invention selectivelyinhibits both ERK1 and ERK2 activity with an IC50 value of about 100 nM,50 nM, 10 nM, 5 nM, 100 pM, 10 pM or even 1 pM, or less as ascertainedin an in vitro kinase assay.

In some embodiments, one or more compounds of the invention competeswith ATP for binding to ATP-binding site on ERK1 and/or ERK2. In someembodiments, one or more compounds of the invention binds to ERK1 and/orERK2 at a site other than the ATP-binding site.

In some embodiments, one or more compounds of the invention are capableof inhibiting and/or otherwise modulating cellular signal transductionvia one or more protein kinases or lipid kinases disclosed herein. Forexample, one or more compounds of the invention are capable ofinhibiting or modulating the output of a signal transduction pathway.Output of signaling transduction of a given pathway can be measured bythe level of phosphorylation, dephosphorylation, fragmentation,reduction, oxidation of a signaling molecule in the pathway of interest.In another specific embodiment, the output of the pathway may be acellular or phenotypic output (e.g. modulating/inhibition of cellularproliferation, cell death, apoptosis, autophagy, phagocytosis, cellcycle progression, metastases, cell invasion, angiogenesis,vascularization, ubiquitination, translation, transcription, proteintrafficking, mitochondrial function, golgi function, endoplasmicreticular function, etc). In some embodiments, one or more compounds ofthe invention are capable of, by way of example, causing apoptosis,causing cell cycle arrest, inhibiting cellular proliferation, inhibitingtumor growth, inhibiting angiogenesis, inhibiting vascularization,inhibiting metastases, and/or inhibiting cell invasion.

In some embodiments, one or more compounds of the invention causesapoptosis of said cell or cell cycle arrest. Cell cycle can be arrestedat the G0/G1 phase, S phase, and/or G2/M phase by the subject compounds.

In some embodiments, one or more compounds of the invention includingbut not limited to the compounds listed above are capable of inhibitingcellular proliferation. For example, in some cases, one or morecompounds of the invention listed in above may inhibit proliferation oftumor cells or tumor cell lines with a wide range of genetic makeup. Insome cases, the compounds of the invention may inhibit PC3 cellproliferation in vitro or in an in vivo model such as a xenograft mousemodel. In some cases, in vitro cultured PC3 cell proliferation may beinhibited with an IC₅₀ of less than 100 nM, 75 nM, 50 nM, 25 nM, 15 nM,10 nM, 5 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM or less by one or morecompounds of the invention listed above.

In some embodiments, proliferation of primary tumors derived fromsubjects (e.g. cancer patients) can be inhibited by a compound of theinvention as shown by in vitro assays, or in vivo models (e.g. using thesubjects' tumor cells for generating a xenograft mode). In some casesprimary tumor cell line proliferation may be inhibited with an IC₅) ofless than 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 3 nM, 2 nM, 1nM, 0.5 nM, 0.1 nM or even less by one or more compounds of theinvention listed in Table 1. In some cases, the average IC₅₀ of acompound of the invention for inhibiting a panel 10, 20, 30, 40, 50, 100or more primary tumor cells may be about 200 nM, 100 nM, 75 nM, 50 nM,25 nM, 15 nM, 10 nM, 5 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM or evenless. The tumor cells that can be inhibited by the compounds of thepresent invention include but are not limited to pancreatic, renal(kidney), bone, nasopharyngeal, gastric, stomach, ovarian, oral, breast,blood, prostate, rectal, colon, colorectal, blial, neural, lung, anddermal cells.

In some embodiments, the compounds of the invention are effective inblocking cell proliferation signals in cells. In some cases, cellproliferation signaling may be inhibited by one or more compounds of theinvention including but not limited to those shown in Table 1 asevidenced by Western blot analysis of phosphorylation of proteins suchas FOXO1 (phosphorylation at T24/3a T32), GSK3β (phosphorylation at S9),PRAS40 (phosphorylation at T246), or MAPK phosphorylation. In somecases, the compounds of the invention can inhibit phosphorylation ofsignaling proteins and suppress proliferation of cells containing thesesignaling proteins but are resistant to existing chemotherapeutic agentsincluding but not limited to rapanycin, Gleevec, dasatinib, alkylatingagents, antimetabolites, anthracyclines, plant alkaloids, topoisomeraseinhibitors and other antitumor agents disclosed herein.

In some embodiments, one or more compounds of the invention includingbut not limited to those listed above may cause cell cycle arrest. Insome cases, cells treated with one or more compounds of the inventionincluding but not limited to those listed above, may arrest or takelonger to proceed through one or more cell cycle stages such as G₀/G₁,S, or G₂/M. For example, cells treated with one or more compounds of theinvention may arrest or take longer to proceed through the G₀/G₁ cellcycle stage. In some cases, about 35%, 40%, 50%, 55%, 60%, 65%, 70% ormore of cells treated with one or more compounds of the invention may bein the G₀/G₁ cell cycle stage. In some cases, cells exhibiting cellcycle arrest in the G₀/G₁ cell cycle stage in response to treatment withthe compounds of the invention are tumor cells or rapidly dividingcells. In some cases, the compounds of the invention affect a comparableor a greater degree of G₀/G₁ arrest as compared to doxorubicin.

In some embodiments, cell signaling in tumor cells xenografted intofemale athymic nude mice may be inhibited by one or more compounds ofthe invention such as the compounds listed above. In some cases, cellsignaling may be inhibited by one or more compounds of the invention asevidenced by western blot detection of phosphorylation of ERK kinase(s)extracted from homogenized tumors. In some cases, inhibition ofphosphorylation may be comparable to or greater than that provided byknown kinase inhibitors that also inhibit one or more isoforms of ERKunder the conditions tested.

In some embodiments, the compounds of the invention including but notlimited to the compounds listed above, cause a reduction in tumor volumeof xenograft tumors in female nude athymic mice. For example, treatmentwith one or more compounds of the invention results in a reduction inthe growth or tumor volume caused by engraftment of A375 (mutant B-RafV600E), LOX (mutant B-Raf V600E) and Colo-205 (mutant B-Raf V600E),PANC-1 (mutant K-Ras G12D), MiaPaca-2 (mutant K-Ras G12C), HCT116(mutant K-Ras G13D), H441 (mutant K-Ras G12V), H23 (mutant K-Ras G12C),MDA-MB-231 (mutant K-Ras G13D)) and LS1034 (mutant N-Ras) tumor cells innude mice. The compounds of the invention may be administered orally,subcutaneously, or intravenously, or any other compound administrationmethods provided herein. In some cases, the compounds are administeredonce a week, every other day, once a day, twice a day, three times aday, four times a day or more. In some cases, 0.01 mg/kg of compound isadministered, 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 1mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 7.5 mg/kg, 10mg/kg, 100 mg/kg or more compound is administered at a time. In somecases, a significant reduction in tumor volume may be detected within 5,10, 15, 20, 25, or 30 days of tumor engraftment.

D. Methods of Treatment

The invention also provides methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to conditions implicated by ERK1,ERK2, Ras, Raf and/or MEK kinase malfunction.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof.

In some embodiments, the method relates to the treatment of a disordersuch as cancer, bone disorder, inflammatory disease, immune disease,nervous system disease, metabolic disease, respiratory disease, andcardiac disease.

In some embodiments, the method relates to the treatment of cancer suchas acute myeloid leukemia, myelodysplastic syndrome (MDS), thymus,brain, lung (NSCLC and SCLC), squamous cell, seminomas, melanoma, skin,eye, retinoblastoma, intraocular melanoma, oral cavity andoropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast,cervical, head, neck, renal, kidney, liver, ovarian, prostate,endometrial, colorectal, esophageal, testicular, gynecological, thyroid,CNS, PNS, AIDS related (e.g. Lymphoma and Kaposi's Sarcoma) orViral-Induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis, or prostate(e.g., benign prostatic hypertrophy (BPH)). In some embodiments, thecancer is melanoma or colorectal cancer.

In some embodiments, the method relates to the treatment of a disease ora condition in a subject with a mutation in the Ras or Raf gene. In somecases, the disease is a cancer and the mutation is in the Ras gene. Forexample, the disease can be a melanoma in a subject with an N-Rasmutation. Alternatively, the disease can be lung cancer or colon cancerin a subject with a K-Ras mutation.

In some embodiments, the method relates to the treatment of a disease ora condition that is resistant to a Ras, Raf and/or MEK inhibitor. Forexample, the disease can be a melanoma that is resistant to a B-Rafand/or MEK inhibitor.

The treatment methods provided herein comprise administering to thesubject a therapeutically effective amount of a compound of theinvention. In one embodiment, the present invention provides a method oftreating an inflammation disorder, including autoimmune diseases in amammal. The method comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof diseases associated with malfunctioning of one ormore types of ERK including but not limited to acute disseminatedencephalomyelitis (ADEM), Addison's disease, antiphospholipid antibodysyndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease,Crohn's disease, Diabetes mellitus (type 1), Goodpasture's syndrome,Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease,lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonusmyoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, oemphigus,polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoidarthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis(also known as “giant cell arteritis”), warm autoimmune hemolyticanemia, Wegener's granulomatosis, alopecia universalis, Chagas' disease,chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitissuppurativa, interstitial cystitis, neuromyotonia, sarcoidosis,scleroderma, ulcerative colitis, vitiligo, and vulvodynia. Otherdisorders include bone-resorption disorders and thrombosis.

In some embodiments, the method of treating inflammatory or autoimmunediseases comprises administering to a subject (e.g. a mammal) atherapeutically effective amount of one or more compounds of the presentinvention that selectively inhibit ERK1 and/or ERK2 as compared to allother kinases in the Ras/Raf/MEK/ERK pathway. Such selective inhibitionof ERK1 and/or ERK2 may be advantageous for treating any of the diseasesor conditions described herein. For example, selective inhibition ofERK2 may inhibit inflammatory responses associated with inflammatorydiseases, autoimmune disease, or diseases related to an undesirableimmune response including but not limited to asthma, emphysema, allergy,dermatitis, rheumatoid arthritis, psoriasis, lupus erythematosus, orgraft versus host disease. Selective inhibition of ERK2 may furtherprovide for a reduction in the inflammatory or undesirable immuneresponse without a concomitant reduction in the ability to reduce abacterial, viral, and/or fungal infection. Selective inhibition of bothERK1 and ERK2 may be advantageous for inhibiting the inflammatoryresponse in the subject to a greater degree than that would be providedfor by inhibitors that selectively inhibit ERK1 or ERK2 alone. In oneaspect, one or more of the subject methods are effective in reducingantigen specific antibody production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more. In another aspect, oneor more of the subject methods are effective in reducing antigenspecific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rheumatoid arthritis including butnot limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%,60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75% 80%, 86%/o, 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%5, 25%, 30%, 40%, 50%,60%, 75%, 80%, 90% or more. In still another aspect, the subject methodsare effective in reducing knee histopathology scores by about 59, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.

In other embodiments, the present invention provides methods of usingthe compounds or pharmaceutical compositions to treat respiratorydiseases including but not limited to diseases affecting the lobes oflung, pleural cavity, bronchial tubes, trachea, upper respiratory tract,or the nerves and muscle for breathing. For example, methods areprovided to treat obstructive pulmonary disease. Chronic obstructivepulmonary disease (COPD) is an umbrella term for a group of respiratorytract diseases that are characterized by airflow obstruction orlimitation. Conditions included in this umbrella term are: chronicbronchitis, emphysema, and bronchiectasis.

In another embodiment, the compounds described herein are used for thetreatment of asthma. Also, the compounds or pharmaceutical compositionsdescribed herein may be used for the treatment of endotoxemia andsepsis. In one embodiment, the compounds or pharmaceutical compositionsdescribed herein are used to for the treatment of rheumatoid arthritis(RA). In yet another embodiment, the compounds or pharmaceuticalcompositions described herein is used for the treatment of contact oratopic dermatitis. Contact dermatitis includes irritant dermatitis,phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis,contact urticaria, systemic contact-type dermatitis and the like.Irritant dermatitis can occur when too much of a substance is used onthe skin of when the skin is sensitive to certain substance. Atopicdermatitis, sometimes called eczema, is a kind of dermatitis, an atopicskin disease.

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof. In some embodiments, said methodis for treating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

Subjects that can be treated with compounds of the invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative of said compounds, according to the methods of this inventioninclude, for example, subjects that have been diagnosed as havingpsoriasis; restenosis; atherosclerosis; BPH; breast cancer such as aductal carcinoma in duct tissue in a mammary gland, medullarycarcinomas, colloid carcinomas, tubular carcinomas, and inflammatorybreast cancer; ovarian cancer, including epithelial ovarian tumors suchas adenocarcinoma in the ovary and an adenocarcinoma that has migratedfrom the ovary into the abdominal cavity; uterine cancer; cervicalcancer such as adenocarcinoma in the cervix epithelial includingsquamous cell carcinoma and adenocarcinomas; prostate cancer, such as aprostate cancer selected from the following: an adenocarcinoma or anadenocarcinoma that has migrated to the bone; pancreatic cancer such asepitheloid carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer; skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; AIDS-relatedlymphoma such as diffuse large B-cell lymphoma, B-cell immunoblasticlymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma;viral-induced cancers including hepatitis B virus (HBV), hepatitis Cvirus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papilloma virus(HPV) and cervical cancer; central nervous system cancers (CNS) such asprimary brain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMiillerian tumor; oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer; stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; andcolon cancer

The invention also relates to a method of treating diabetes in a mammalthat comprises administering to said mammal a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof.

In addition, the compounds described herein may be used to treat acne.

In addition, the compounds described herein may be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

Further the compounds described herein may be used for the treatment ofglomerulonephritis. Glomerulonephritis is a primary or secondaryautoimmune renal disease characterized by inflammation of the glomeruli.It may be asymptomatic, or present with hematuria and/or proteinuria.There are many recognized types, divided in acute, subacute or chronicglomerulonephritis. Causes are infectious (bacterial, viral or parasiticpathogens), autoimmune or paraneoplastic.

Additionally, the compounds described herein may be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), addison's disease, antiphospholipid antibody syndrome (APS),aplastic anemia, autoimmune hepatitis, coeliac disease, crohn's disease,diabetes mellitus (type 1), goodpasture's syndrome, graves' disease,guillain-barré syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonussyndrome (OMS), optic neuritis, ord's thyroiditis, ostheoarthritis,uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,reiter's syndrome, takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, wegener's granulomatosis, alopeciauniversalis, chagas' disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovasculardisease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. Examples of cardiovascular conditions include, butare not limited to, atherosclerosis, restenosis, vascular occlusion andcarotid obstructive disease.

In another aspect, the invention provides methods of disrupting thefunction of a leukocyte or disrupting a function of an osteoclast. Themethod includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound of the invention.

In another aspect of the present invention, methods are provided fortreating ophthalmic disease by administering one or more compounds ofthe invention or pharmaceutical compositions to the eye of a subject.

Methods are further provided for administering the compounds of thepresent invention via eye drop, intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds of the present invention are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film. It is contemplated that all localroutes to the eye may be used including topical, subconjunctival,periocular, retrobulbar, subtenon, intracameral, intravitreal,intraocular, subretinal, juxtascleral and suprachoroidal administration.Systemic or parenteral administration may be feasible including but notlimited to intravenous, subcutaneous, and oral delivery. An exemplarymethod of administration will be intravitreal or subtenon injection ofsolutions or suspensions, or intravitreal or subtenon placement ofbioerodible or non-bioerodible devices, or by topical ocularadministration of solutions or suspensions, or posterior juxtascleraladministration of a gel or cream formulation.

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic surfactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quaternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium compound is a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, myristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

The invention further provides methods of modulating a ERK kinaseactivity by contacting the kinase with an effective amount of a compoundof the invention. Modulation can be inhibiting or activating kinaseactivity. In some embodiments, the invention provides methods ofinhibiting kinase activity by contacting the kinase with an effectiveamount of a compound of the invention in solution. In some embodiments,the invention provides methods of inhibiting the kinase activity bycontacting a cell, tissue, organ that express the kinase of interest. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in subject including but not limited to rodents and mammal(e.g., human) by administering into the subject an effective amount of acompound of the invention. In some embodiments, the percentage ofinhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the kinase is selected from the group consisting ofERK, including different isoforms such as ERK1 and ERK2; Ras; Raf; JNK;ErbB-1 (EGFR); Her2 (ErbB-2); Her 3 (ErbB-3); Her 4 (ErbB-4); MAP2K1(MEK1); MAP2K2 (MEK2); MAP2K3 (MEK3); MAP2K4 (MEK4); MAP2K5 (MEK5),MAP2K6 (MEK6); MAP2K7 (MEK7); CDK1; CDK2; CDK3; CDK4; CDK5; CDK6; CDK7;CDK8; CDK9; CDK11.

The invention further provides methods of modulating ERK activity bycontacting ERK with an amount of a compound of the invention sufficientto modulate the activity of ERK. Modulate can be inhibiting oractivating ERK activity. In some embodiments, the invention providesmethods of inhibiting ERK by contacting ERK with an amount of a compoundof the invention sufficient to inhibit the activity of ERK. In someembodiments, the invention provides methods of inhibiting ERK activityin a solution by contacting said solution with an amount of a compoundof the invention sufficient to inhibit the activity of ERK in saidsolution. In some embodiments, the invention provides methods ofinhibiting ERK activity in a cell by contacting said cell with an amountof a compound of the invention sufficient to inhibit the activity of ERKin said cell. In some embodiments, the invention provides methods ofinhibiting ERK activity in a tissue by contacting said tissue with anamount of a compound of the invention sufficient to inhibit the activityof ERK in said tissue. In some embodiments, the invention providesmethods of inhibiting ERK activity in an organism by contacting saidorganism with an amount of a compound of the invention sufficient toinhibit the activity of ERK in said organism. In some embodiments, theinvention provides methods of inhibiting ERK activity in an animal bycontacting said animal with an amount of a compound of the inventionsufficient to inhibit the activity of ERK in said animal. In someembodiments, the invention provides methods of inhibiting ERK activityin a mammal by contacting said mammal with an amount of a compound ofthe invention sufficient to inhibit the activity of ERK in said mammal.In some embodiments, the invention provides methods of inhibiting ERKactivity in a human by contacting said human with an amount of acompound of the invention sufficient to inhibit the activity of ERK insaid human. The present invention provides methods of treating a diseasemediated by ERK activity in a subject in need of such treatment.

The present invention also provides methods for combination therapies inwhich an agent known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target enzymes are used incombination with a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. In one aspect, such therapy includes but is notlimited to the combination of one or more compounds of the inventionwith chemotherapeutic agents, therapeutic antibodies, and radiationtreatment, to provide a synergistic or additive therapeutic effect.

In one aspect, the compounds or pharmaceutical compositions of theinvention may present synergistic or additive efficacy when administeredin combination with agents that inhibit IgE production or activity. Suchcombination can reduce the undesired effect of high level of IgEassociated with the use of one or more ERK inhibitors, if such effectoccurs. This may be useful in treatment of autoimmune and inflammatorydisorders (AIID) such as rheumatoid arthritis.

For treatment of autoimmune diseases, the compounds of the invention orpharmaceutical compositions can be used in combination with commonlyprescribed drugs including but not limited to Enbrel®, Remicade®,Humira®, Avonex®, and Rebif®. For treatment of respiratory diseases, thecompounds of the invention or pharmaceutical compositions can beadministered in combination with commonly prescribed drugs including butnot limited to Xolair®, Advair®, Singulair®, and Spiriva®.

The compounds of the invention may be formulated or administered inconjunction with other agents that act to relieve the symptoms ofinflammatory conditions such as encephalomyelitis, asthma, and the otherdiseases described herein. These agents include non-steroidalanti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen;naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids areused to reduce inflammation and suppress activity of the immune system.The most commonly prescribed drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be veryuseful in some individuals with lupus. They are most often prescribedfor skin and joint symptoms of lupus. Azathioprine (Imuran) andcyclophosphamide (Cytoxan) suppress inflammation and tend to suppressthe immune system. Other agents, e.g. methotrexate and cyclosporin areused to control the symptoms of lupus. Anticoagulants are employed toprevent blood from clotting rapidly. They range from aspirin at very lowdose which prevents platelets from sticking, to heparin/coumadin.

In another aspect, this invention also relates to methods andpharmaceutical compositions for inhibiting abnormal cell growth in amammal which comprises an amount of a compound of the invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, in combination with an amount of an anti-canceragent (e.g. a chemotherapeutic agent). Many chemotherapeutics arepresently known in the art and can be used in combination with thecompounds of the invention.

In some embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlomaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidainol; nitractine; pentostatin; phenamet; pirarubicin;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Iniquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126, andZosuquidar.

This invention further relates to a method for using the compounds orpharmaceutical compositions provided herein, in combination withradiation therapy for inhibiting abnormal cell growth or treating thehyperproliferative disorder in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound of the invention in this combination therapy can be determinedas described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention or pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which amount is effective issensitizing abnormal cells to treatment with radiation. The amount ofthe compound, salt, or solvate in this method can be determinedaccording to the means for ascertaining effective amounts of suchcompounds described herein.

The compounds or pharmaceutical compositions of the invention can beused in combination with an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the invention and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998). WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998). European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the invention areAG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

The invention also relates to a method of and to a pharmaceuticalcomposition for treating a cardiovascular disease in a mammal whichcomprises an amount of a compound of the invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, or an isotopically-labeled derivative thereof, andan amount of one or more therapeutic agents use for the treatment ofcardiovascular diseases.

Exemplary agents for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings comprised by the invention. Moreover, a coating can be used toeffect therapeutic delivery focally within the vessel wall. Byincorporation of the active agent in a swellable polymer, the activeagent will be released upon swelling of the polymer.

The compounds described herein may be formulated or administered inconjunction with liquid or solid tissue barriers also known aslubricants. Examples of tissue barriers include, but are not limited to,polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.

Medicaments which may be administered in conjunction with the compoundsdescribed herein include any suitable drugs usefully delivered byinhalation for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;anti-infectives, e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines or pentamidine; antihistamines, e.g.methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide,budesonide, tipredane, triamcinolone acetonide or fluticasone;antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine,adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol,orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimize the activity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eieosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, Mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundof the invention include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab trastuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

Further therapeutic agents that can be combined with a compound of theinvention may be found in Goodman and Gilman's “The PharmacologicalBasis of Therapeutics” Tenth Edition edited by Hardman, Limbird andGilman or the Physician's Desk Reference, both of which are incorporatedherein by reference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds of the invention will be co-administered with other agents asdescribed above. When used in combination therapy, the compoundsdescribed herein may be administered with the second agentsimultaneously or separately. This administration in combination caninclude simultaneous administration of the two agents in the same dosageform, simultaneous administration in separate dosage forms, and separateadministration. That is, a compound described herein and any of theagents described above can be formulated together in the same dosageform and administered simultaneously. Alternatively, a compound of theinvention and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentinvention can be administered just followed by and any of the agentsdescribed above, or vice versa. In the separate administration protocol,a compound of the invention and any of the agents described above may beadministered a few minutes apart, or a few hours apart, or a few daysapart.

Administration of the compounds of the present invention can be effectedby any method that enables delivery of the compounds to the site ofaction. An effective amount of a compound of the invention may beadministered in either single or multiple doses by any of the acceptedmodes of administration of agents having similar utilities, includingrectal, buccal, intranasal and transdermal routes, by intra-arterialinjection, intravenously, intraperitoneally, parenterally,intramuscularly, subcutaneously, orally, topically, as an inhalant, orvia an impregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer.

The amount of the compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate. A single dose of a compound ofthe invention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the agents of the invention may continue as long asnecessary. In some embodiments, an agent of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, an agent of the invention is administered for less than 28,14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of theinvention is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

When a compound of the invention is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention, unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The compounds described herein can be used in combination with otheragents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments, the one or morecompounds of the invention will be co-administered with other agents asdescribed above. In some embodiments, the other agent is an anti-canceragent. When used in combination therapy, the compounds described hereinmay be administered with the second agent simultaneously, or separately.The administration in combination can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, or separate administration.That is, a compound described herein and any of the agents describedabove can be formulated together in the same dosage form andadministered simultaneously. Alternatively, a compound of the inventionand any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentinvention can be administered just followed by and any of the agentsdescribed above, or vice versa. In the separate administration protocol,a compound of the invention and any of the agents described above may beadministered a few minutes apart, or a few hours apart, or a few daysapart.

E. Pharmaceutical Compositions and Kits

The invention provides a pharmaceutical composition comprising one ormore compounds disclosed herein. In some embodiments the inventionprovides pharmaceutical compositions for the treatment of disorders suchas hyperproliferative disorders including but not limited to cancerssuch as acute myeloid leukemia, lymphoma, thymus, brain, lung (NSCLCand/or SCLC), squamous cell, skin, eye, retinoblastoma, intraocularmelanoma, mesothelioma, mediastinum, oral cavity and oropharyngeal,bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head,neck, renal, kidney, liver, hepatobiliary system, small intestine,colon, rectum, anus, prostate, colorectal, endometrial, urethra,esophageal, testicular, gynecological, penis, testis, ovarian, endocrinesystem, skin, thyroid, CNS, PNS, AIDS related AIDS-Related (e.g.Lymphoma and Kaposi's Sarcoma), other viral-induced cancers, sarcomas ofthe soft tissue and bone, and melanomas of cutaneous and intraocularorigin. Cancers includes solid tumors as well as hematologicalmalignancies. In addition, a cancer at any stage of progression can betreated, such as primary, metastatic, and recurrent cancers.

In some embodiments, said pharmaceutical composition is for thetreatment of a non-cancerous hyperproliferative disorder such as abenign tumor, for example but not limited to, for the treatment of abenign hyperplasia of the skin (e.g., psoriasis), breast, lung, kidney,pancreas, restenosis, or prostate (e.g., benign prostatic hypertrophy(BPH)).

In some embodiments, the invention provides pharmaceutical compositionsfor treating diseases or conditions related to an undesirable,over-active, harmful or deleterious immune response in a mammal. Suchundesirable immune response can be associated with or result in e.g.asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis,auto-immune diseases, rhuematoid arthritis, graft versus host disease,and lupus erythematosus. The pharmaceutical compositions of the presentinvention can be used to treat other respiratory diseases including butnot limited to disease affecting the lobes of the lung, the pleuralcavity, bronchial tubes, trachea, upper respiratory tract, or the nervesand muscle responsible for breathing.

The invention also provides compositions for the treatment of multiorganfailure.

The invention also provides compositions for the treatment of liverdiseases (including diabetes), pancreatitis, gall bladder disease(including gallstones), or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or pain in amammal.

The invention further provides a composition for the prevention ofblastocyte implantation in a mammal.

The invention also relates to a composition for treating a diseaserelated to vasculogenesis or angiogenesis in a mammal, which canmanifest as tumor angiogenesis, chronic inflammatory disease such asrheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skindiseases such as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age -related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The invention further provides compositions for the treatment ofdisorders involving platelet aggregation or platelet adhesion, includingbut not limited to Bernard-Soulier syndrome, Glanzmann's thrombasthenia,Scott's syndrome, von Willebrand disease, Hermansky-Pudlak Syndrome, andGray platelet syndrome.

In some embodiments, compositions are provided for treating a diseasewhich is skeletal muscle atrophy, skeletal or muscle hypertrophy. Theinvention further provides compositions for the treatment of disordersthat include but are not limited to cancers as discussed herein,transplantation-related disorders (e.g., lowering rejection rates,graft-versus-host disease, etc.), muscular sclerosis (MS), allergicdisorders (e.g. arthritis, allergic encephalomyelitis) and otherimmunosuppressive-related disorders, metabolic disorders (e.g.,diabetes), reducing intimal thickening following vascular injury, andmisfolded protein disorders (e.g., Alzheimer's Disease, Gaucher'sDisease, Parkinson's Disease, Huntington's Disease, cystic fibrosis,macular degeneration, retinitis pigmentosa, and prion disorders). Thedisorders also include hamartoma syndromes, such as tuberous sclerosisand Cowden Disease (also termed Cowden syndrome and multiple hamartomasyndrome)

In some embodiments, the invention provides a pharmaceutical compositionfor treating ophthalmic disorders. The composition is formulated forocular administration and it contains an effective amount of a compoundof the present invention and a pharmaceutical excipient suitable forocular administration. Pharmaceutical compositions of the inventionsuitable for ocular administration can be presented as discrete dosageforms, such as drops or sprays each containing a predetermined amount ofan active ingredient a solution, or a suspension in an aqueous ornon-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquidemulsion. Eye drops may be prepared by dissolving the active ingredientin a sterile aqueous solution such as physiological saline, bufferingsolution, etc., or by combining powder compositions to be dissolvedbefore use. Other vehicles may be chosen, as is known in the art,including but not limited to: balance salt solution, saline solution,water soluble polyethers such as polyethyene glycol, polyvinyls, such aspolyvinyl alcohol and povidone, cellulose derivatives such asmethylcellulose and hydroxypropyl methylcellulose, petroleum derivativessuch as mineral oil and white petrolatum, animal fats such as lanolin,polymers of acrylic acid such as carboxypolymethylene gel, vegetablefats such as peanut oil and polysaccharides such as dextrans, andglycosaminoglycans such as sodium hyaluronate. If desired, additivesordinarily used in the eye drops can be added. Such additives includeisotonizing agents (e.g., sodium chloride, etc.), buffer agent (e.g.,boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate,etc.), preservatives (e.g., benzalkonium chloride, benzethoniumchloride, chlorobutanol, etc.), thickeners (e.g., saccharide such aslactose, mannitol, maltose, etc.; e.g., hyaluronic acid or its salt suchas sodium hyaluronate, potassium hyaluronate, etc.; e.g.,mucopolysaccharide such as chondroitin sulfate, etc.; e.g., sodiumpolyacrylate, carboxyvinyl polymer, crosslinked polyacrylate, polyvinylalcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propylmethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose or other agents known to those skilled in theart).

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentinvention as the active ingredient, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof. Wheredesired, the pharmaceutical compositions contain pharmaceuticallyacceptable salt and/or coordination complex thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the one or more compounds of the invention and other agent(s) may bemixed into a preparation or both components may be formulated intoseparate preparations to use them in combination separately or at thesame time.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is less than100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%,0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.0060%, 0.005%, 0.004%, 0.003%,0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.00040%,0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is greaterthan 90%, 80%, 70%, 60%, 50%, 40%, 30, 20%, 19.75%, 19.50%, 19.25% 19%,18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25% 17% 16.75%, 16.50%,16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50, 14.25% 14,13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75, 11.50%,11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75% 9.50%, 9.25, 8.75, 8.50,8.25% 8, 7.75, 7.50% 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%,5.25, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%,2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.40%, 0.3%, 0.2, 0.1,0.090%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%,0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%,0.0008%, 0,0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0002%, or 0.0001%w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is in therange from approximately 0.0001% to approximately 50%, approximately0.001% to approximately 40%, approximately 0.01% to approximately 30%,approximately 0.02% to approximately 29%, approximately 0.03% toapproximately 28%, approximately 0.04% to approximately 27%,approximately 0.05% to approximately 26%, approximately 0.06% toapproximately 25%, approximately 0.07% to approximately 24%,approximately 0.08% to approximately 23%, approximately 0.09% toapproximately 22%, approximately 0.1% to approximately 21%,approximately 0.2% to approximately 20%, approximately 0.3% toapproximately 19%, approximately 0.4% to approximately 18%,approximately 0.5% to approximately 17%, approximately 0.6% toapproximately 16%, approximately 0.7% to approximately 15%,approximately 0.8% to approximately 14%, approximately 0.9% toapproximately 12%, approximately 1% to approximately 10% w/w, w/v orv/v.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is in therange from approximately 0.001% to approximately 10%, approximately0.01% to approximately 5%, approximately 0.02% to approximately 4.5%,approximately 0.03 to approximately 4%, approximately 0.04% toapproximately 3.5%, approximately 0.05% to approximately 3%,approximately 0.06% to approximately 2.5%, approximately 0.07% toapproximately 2%, approximately 0.08% to approximately 1.5%,approximately 0.09% to approximately 1%, approximately 0.1% toapproximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds provided in thepharmaceutical compositions of the present invention is equal to or lessthan 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 15 g, 1.0 g, 0.95 g,0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 055 g, 0.5 g, 0.45g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 01 g, 0.09 g, 0.08 g,0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g,or 0.0001 g.

In some embodiments, the amount of one or more compounds provided in thepharmaceutical compositions of the present invention is more than 0.0001g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g,0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g,0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g,0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g,0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more compounds of theinvention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg per day, from 0.1 to 500 mg, from 0.5 to 100 mg,from 1 to 50 mg per day, from 2 to 40 mg per day, from 3 to 30 mg perday, from 4 to 20 mg per day, and from 5 to 10 mg per day are examplesof dosages that may be used. The exact dosage will depend upon the routeof administration, the form in which the compound is administered, thesubject to be treated, the body weight of the subject to be treated, andthe preference and experience of the attending physician.

A pharmaceutical composition of the invention typically contains anactive ingredient (e.g., a compound) of the present invention or apharmaceutically acceptable salt and/or coordination complex thereof,and one or more pharmaceutically acceptable excipients, carriers,including but not limited to inert solid diluents and fillers, diluents,sterile aqueous solution and various organic solvents, permeationenhancers, solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

In some embodiments, the invention provides a pharmaceutical compositionfor oral administration containing a compound of the invention, and apharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a compound of the invention; optionally (ii) an effective amount of asecond agent; and (iii) a pharmaceutical excipient suitable for oraladministration. In some embodiments, the composition further contains:(iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time anhydrouspharmaceutical compositions and dosage forms of the invention can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the invention which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) maybe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used may vary based upon the type of formulationand mode of administration, and may be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, maybe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms of theinvention include, but are not limited to, agar-agar, alginic acid,calcium carbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions.

Hydrophilic surfactants are generally considered to be those compoundshaving an HLB value greater than about 10, as well as anionic, cationic,or zwitterionic compounds for which the HLB scale is not generallyapplicable. Similarly, lipophilic (i.e., hydrophobic) surfactants arecompounds having an HLB value equal to or less than about 10. However,HLB value of a surfactant is merely a rough guide generally used toenable formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acyl lactylates; mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof polyoxyethylated vitaminsand derivatives thereof, polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation.PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrosemonolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use, e.g., compositions for injection. A solubilizer may alsobe added to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, 8-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, e-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, -butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a subjectusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 100%, or up to about 200% by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may include,but not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

In some embodiments, the invention provides a pharmaceutical compositionfor injection containing a compound of the present invention and apharmaceutical excipient suitable for injection. Components and amountsof agents in the compositions are as described herein.

The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present invention in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

In some embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing a compound of the present inventionand a pharmaceutical excipient suitable for transdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound of the present invention in controlled amounts,either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver Formulation inan appropriate manner.

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G,eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002;Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety.

Administration of the compounds or pharmaceutical composition of thepresent invention can be effected by any method that enables delivery ofthe compounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g. transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. Compounds can also be administered intraadiposallyor intrathecally.

The amount of the compound administered will be dependent on the subjectbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration can be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes known in the art or disclosed herein may be used asappropriate. A single dose of a compound of the invention may also beused for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the compounds of the invention may continue as long asnecessary. In some embodiments, a compound of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, a compound of the invention is administered for less than28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound ofthe invention is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyvanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. Compounds of the invention may beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, thecompound may be located in the body of the stent or graft, for examplein microchannels or micropores. When implanted, the compound diffusesout of the body of the stent to contact the arterial wall. Such stentsmay be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of the compound of theinvention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additionalbrief solvent wash. In yet other embodiments, compounds of the inventionmay be covalently linked to a stent or graft. A covalent linker may beused which degrades in vivo, leading to the release of the compound ofthe invention. Any bio-labile linkage may be used for such a purpose,such as ester, amide or anhydride linkages. Compounds of the inventionmay additionally be administered intravascularly from a balloon usedduring angioplasty. Extravascular administration of the compounds viathe pericard or via advential application of formulations of theinvention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; 5,674,278; 5,879,382; 6,344,053.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

The invention also provides kits. The kits include a compound orcompounds of the present invention as described herein, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Such kits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. The kit may further contain another agent. In someembodiments, the compound of the present invention and the agent areprovided as separate compositions in separate containers within the kit.In some embodiments, the compound of the present invention and the agentare provided as a single composition within a container in the kit.Suitable packaging and additional articles for use (e.g., measuring cupfor liquid preparations, foil wrapping to minimize exposure to air, andthe like) are known in the art and may be included in the kit. Kitsdescribed herein can be provided, marketed and/or promoted to healthproviders, including physicians, nurses, pharmacists, formularyofficials, and the like. Kits may also, in some embodiments, be marketeddirectly to the consumer.

Examples

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods of usingand preparing such compounds. It is to be understood that the scope ofthe present invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Example 1. Synthesis of(6-benzyl-3-(pyridin-4-yl)-1,5,68-tetrahydro-7H-pyrazolo[4,3-g]quinazolin-7-one)

3-bromo-5-methyl-6-nitro-1H-indazole (EX 1-2)

To a stirred solution of 5-methyl-6-nitro-1H-indazole (1.77 g, 10 mmol)in 20 mL of dry DMF at room temperature, NBS (2.14 g, 12 mmol) was addedfollowed by KOH (1.12 g, 20 mmol). The reaction mixture was stirred atthe same temperature overnight. The reaction mixture was diluted withethyl acetate, washed with water and saturated NH₄Cl aqueous solution.The organic solution was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give the desired product (3.1 g) as a brownsolid, which was used in the next step without further purification.

3-bromo-5-methyl-6-nitro-1-trityl-1H-indazole (EX 1-3)

To a stirred solution of 3-bromo-5-methyl-6-nitro-1H-indazole (2.43 g,9.5 mmol) in 30 mL of dry THF at 0° C., NaH (60% in mineral oil, 0.76 g,19 mmol) was added and the reaction mixture was stirred at the sametemperature for 30 min. TrtCl (3.97 g, 14.25 mmol) was added. Thereaction mixture was stirred at room temperature for 6 h. Solvent wasremoved. The residue was dissolved in ethyl acetate and washed withbrine. The organic solution was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The residue was purified by Biotage (25 gcartridge, 0-30% ethyl acetate in hexane) to afford the desired product(4.5 g, 95% yield) as a yellow solid.

5-methyl-6-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazol (EX 1-4)

To a solution of 3-bromo-5-methyl-6-nitro-1-trityl-1H-indazole (2.0 g,4.0 mmol) and pyridin-4-ylboronic acid (736 mg, 6.0 mmol) in 30 mL of4:1 mixture of dioxane and water at room temperature, PdCl₂(dppf) (327mg, 0.40 mmol) and K₂CO₃ (1.10 g, 8.0 mmol) were added. The reactionmixture was degassed and backfilled with nitrogen. The reaction mixturewas stirred at 80° C. overnight. Solvent was removed and the residue wastaken with ethyl acetate. The mixture was filtered through a pad ofCelite and the filtrate was washed with brine. The organic solution wasdried over anhydrous MgSO₄, filtered and concentrated. The residue waspurified on Biotage (25 g cartridge, 10-80% ethyl acetate in hexane) togive the desired product (1.12 g, 56% yield). ESI-MS m/z: 497 [M+H]⁺

N-benzyl-1-(6-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)methenamine(EX 1-6)

To a solution of 5-methyl-6-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazole(222 mg, 0.45 mmol) and NBS (239 mg, 1.35 mmol) in 10 mL of CCl₄ at roomtemperature, AIBN (22 mg, 0.30 mmol) was added. The reaction mixture wasstirred at 80° C. for 2 h. The mixture was cooled down to roomtemperature, and then benzylamine (1.64 mL, 15 mmol) was added. Theresulting mixture was stirred at the same temperature for 3 h. Solventwas removed and the residue was taken with ethyl acetate, washed withsaturated NH₄Cl aqueous solution and brine. The organic solution wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by prep-HPLC to give the desired product (58 mg,21% yield). ESI-MS m/z: 602 [M+H]+.

5-((benzylamino)methyl)-3-(pyridin-4-yl)-1-trityl-1H-indazol-6-amine (EX1-7)

To a solution ofN-benzyl-1-(6-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)methanamine(60 mg, 0.10 mmol) in 3 mL of 1:5 AcOH/2-PrOH mixture at roomtemperature, Zn dust (130 mg, 2.0 mmol) was added. The reaction mixturewas stirred at 60° C. for 3 h. The reaction mixture was cooled to roomtemperature. Solid was removed by filtration and the filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC to give thedesired product (36 mg, 63% yield). ESI-MS m/z: 572 [M+Hi].

6-benzyl-3-(pyridin-4-yl)-1-trityl-1,5,6,8-tetrahydro-7H-pyrazolo[4,3-g]quinazolin-7-one(EX 1-8)

To a solution of5-((benzylamino)methyl)-3-(pyridin-4-yl)-1-trityl-1H-indazol-6-amine (24mg, 0.04 mmol) in 3 mL of DCM, Et₃N (42 μL, 0.24 mmol) was addedfollowed by CDI (65 mg, 0.40 mmol). The reaction mixture was stirred atroom temperature for 3 h. The mixture was concentrated in vacuo and theresidue was used in the next step without further purification. ESI-MSm/z: 598 [M+H]⁺.

6-benzyl-3-(pyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[4,3-g]quinazolin-7-one(1)

To a solution of6-benzyl-3-(pyridin-4-yl)-1-trityl-1,5,6,8-tetrahydro-7H-pyrazolo[4,3-g]quinazolin-7-one(crude obtained from previous step) in 4 mL of DCM, 1 mL of TFA wasadded. The reaction mixture was stirred at room temperature for 30 min.Solvent was removed and the residue was purified by prep-HPLC to givethe desired product (8 mg, 56% yield, 2 steps). ¹H NMR (400 MHz,DMSO-d6) δ: 13.25 (br, 1H), 9.62 (s, 1H), 8.63 (dd, J=1.4, 4.6 Hz, 1H),7.92-7.95 (m, 3H), 7.29-7.37 (m, 5H), 6.98 (s, 1H), 4.60 (s, 2H), 4.45(s, 2H). ESI-MS m/z: 356.0 [M+H]⁺.

Example 2. Synthesis of((R)-3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one)

5-bromo-3-iodo-6-nitro-1H-indazole (EX 2-2)

To a stirred mixture of 5-bromo-6-nitro-1H-indazole (3.5 g, 14.5 mmol)in DMF (50 mL) at room temperature, KOH (2.84 g, 50.6 mmol, 3.5 eq) wasadded and the resulting mixture was stirred at room temperature for 10min. NIS (3.58 g, 15.91 mmol, 1.1 eq) was added to the reaction mixture.The resulting mixture was stirred at room temperature for 10 h. Thereaction mixture was poured into water (100 mL) and extracted with ethylacetate (200 mL×3). The combined organic layers were washed with H₂O(200 mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford the desired product (4.2 g, 79% yield) as a yellowsolid. The crude product was used directly in the next step withoutfurther purification.

5-bromo-3-iodo-6-nitro-1-trityl-1H-indazole (EX 2-3)

To a stirred mixture of 5-bromo-3-iodo-6-nitro-1H-indazole (1 g, 2.7mmol) in THF (10 mL) at room temperature, NaH (162 mg, 4.08 mmol) wasadded and the resulting reaction mixture was stirred at room temperaturefor 30 min under a nitrogen atmosphere. To this mixture, Trt-Cl (912 mg,3.27 mmol) was added. The resulting mixture was stirred at roomtemperature for 2 h. The reaction mixture was poured into water (30 mL)and extracted with ethyl acetate (80 mL×3). The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (5-20% ethyl acetate/petroleum ether) toafford the desired product (1.6 g, 96% yield) as a yellow solid.

5-bromo-3-iodo-1-trityl-1H-indazol-6-amine (EX 2-4)

To a stirred mixture of 5-bromo-3-iodo-6-nitro-1-trityl-1H-indazole(1.15 g, 1.89 mmol) in HOAc/H₂O (16 mL/4 mL) at 60° C., Fe powder (530mg, 9.46 mmol) was added. The reaction mixture was stirred at 60° C. for6 h, and then was allowed to cool to room temperature. The reactionmixture was filtered through silica gel and rinsed with ethyl acetate(100 mL). The combined filtrate was extracted with ethyl acetate (80mL×3). The combined organic layer was washed with H₂O (80 mL×3), driedover anhydrous Na₂SO₄, filtrated and concentrated in vacuo to afford thedesired product (750 mg, 69% yield) as a yellow solid. The crude productobtained was used directly in the next step without furtherpurification.

N-(5-bromo-3-iodo-1-trityl-1H-indazol-6-yl)acetamide (EX 2-5)

To a stirred mixture of 5-bromo-3-iodo-1-trityl-1H-indazol-6-amine (346mg, 0.6 mmol) in DCM (10 mL) at 0° C. Et₃N (91 mg, 0.9 mmol) was added.The mixture was stirred at 0° C. for 30 min, and then a solution ofacetyl chloride (61 mg, 0.78 mmol) in DCM (5 mL) was added dropwise. Theresulting mixture was stirred at room temperature for 3 h. The reactionmixture was poured into water (20 mL) and extracted with DCM (50 mL×3).The combined organic layer was washed with brine (50 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to afford thedesired product (350 mg, 95% yield) as a yellow solid. The productobtained was used directly in the next step without furtherpurification.

N-(5-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)acetamide(EX 2-6)

To a mixture of N-(5-bromo-3-iodo-1-trityl-1H-indazol-6-yl)acetamide(173 mg, 0.278 mmol) and 2-methylpyridin-4-ylboronic acid (42 mg, 0.306mmol) in 1,4-dioxane/H₂O (8 mL/2 mL), PdCl₂dppf (31 mg, 0.042 mmol) andK₃PO₄.3H₂O (222 mg, 0.834 mmol) were added sequentially. The resultingmixture was degassed and back-filled with argon three times and thenstirred at 85° C. for 4 h. The mixture was allowed to cool to roomtemperature. The reaction mixture was poured into water (20 mL) andextracted with ethyl acetate (60 mL×3). The combined organic layer waswashed with brine (60 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (10-40% ethyl acetate/petroleum ether) toafford the desired product (46 mg, 35% yield) as a white solid.

N-(3-(2-methylpyridin-4-yl)-1-trityl-5-vinyl-1H-indazol-6-yl)acetamide(EX 2-7)

To A mixture ofN-(5-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)acetamide(46 mg, 0.0785 mmol) and Pd(PPh₃)₄ (18 mg, 0.016 mmol) in toluene (6mL), Tributyl(vinyl)tin (30 mg, 0.094 mmol) was added. The resultingmixture was degassed and back-filled with argon three times and thenstirred at 115° C. for 4 h. The reaction mixture was allowed to cool toroom temperature, poured into water (20 mL) and then extracted withethyl acetate (60 mL×3). The combined organic layer was washed withbrine (60 mL×3), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by flash column chromatography onsilica gel (20-50% ethyl acetate/petroleum ether) to afford the desiredproduct (30 mg, 90% yield) as a white solid.

N-(5-formyl-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)acetamide(EX 2-8)

To a stirred mixture ofN-(3-(2-methylpyridin-4-yl)-1-trityl-5-vinyl-1H-indazol-6-yl)acetamide(28 mg, 0.0524 mmol) in THF (4 mL) and H₂O (1 mL) at 0° C., Osmiumtetroxide (5 mg) was added and the resulting mixture was stirred at 0°C. for 1 h. To this mixture, sodium periodate (56 mg, 0.262 mmol) wasadded. The resulting mixture was stirred at room temperature overnight.The mixture was poured into water (10 mL) and extracted with ethylacetate (50 mL×3). The combined organic layer was washed with brine (50mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(30-60% ethyl acetate/petroleum ether) to afford the desired product (20mg, 80% yield) as a white solid.

(R)—N-(3-(2-methylpyridin-4-yl)-5-((1-phenylethylamino)methyl)-1-trityl-1H-indazol-6-yl)acetamide(EX 2-9)

A mixture ofN-(5-formyl-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)acetamide(84 mg, 0.157 mmol) and (R)-1-phenylethanamine (21 mg, 0.172 mmol) inEtOH was stirred at reflux for 3 h. The mixture was allowed to cool toroom temperature, and then NaBH₄ (12 mg, 0.31 mmol) was added. Thereaction mixture was stirred for 4 h, poured into water (10 mL) andextracted with ethyl acetate (40 mL×3). The combined organic layer waswashed with brine (40 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the desired product (80 mg, 65% yield)as a white solid. The product obtained was used directly in the nextstep without further purification.

(R)-3-(2-methylpyridin-4-yl)-5-((1-phenylethylamino)methyl)-1H-indazol-6-amine(EX 2-10)

A mixture of(R)—N-(3-(2-methylpyridin-4-yl)-5-((1-phenylethylamino)methyl)-1-trityl-1H-indazol-6-yl)acetamide(40 mg, 0.062 mmol) in 6N HCl (5 mL) was stirred at reflux for 5 h. Themixture was allowed to cool to 0° C., K₂CO₃ was added to adjust the PHto 9. The mixture was extracted with ethyl acetate (40 mL×3). Thecombined organic layer was washed with brine (40 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to afford thedesired product (30 mg, 85% yield) as a white solid. The productobtained was used directly in the next step without furtherpurification.

(R)-3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-5,6-dihydro-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(2)

To a mixture of(R)-3-(2-methylpyridin-4-yl)-5-((1-phenylethylamino)methyl)-1H-indazol-6-amine(30 mg, 0.084 mmol) in THF (5 mL), CDI (21 mg, 0.12 mmol) was added. Theresulting mixture was stirred at 70° C. for 5 h. The mixture was cooledto room temperature, poured into water (10 mL) and extracted with ethylacetate (30 mL×3). The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (2-10%MeOH/DCM) to afford the desired product (10 mg, 31% yield) as a whitesolid. ¹H NMR (300 MHz, DMSO-d6) δ: 13.25 (s, 1H), 9.57 (s, 1H), 8.48(d, J=5.4 Hz, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.73 (d, J=5.1 Hz, 1H),7.38 (m, 4H), 7.28 (m, 1H), 6.97 (s, 1H), 5.76 (m, 1H), 4.56 (d, J=4.7Hz, 1H), 4.01 (d, J=4.9 Hz, 1H), 2.54 (s, 3H), 1.57 (d, J=7.2 Hz, 3H).ESI-MS m/z: 384.3 [M+H]⁺.

Example 3: Synthesis of6-(4-fluorobenzyl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-oneN-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)(4-fluorophenyl)methanamine

To a solution of 3-bromo-5-methyl-6-nitro-1-trityl-1H-indazole (500 mg,1.0 mmol) and NBS (268 mg, 1.5 mmol) in 10 mL of CCl₄ at roomtemperature, AIBN (98 mg, 0.6 mmol) was added. The reaction mixture wasstirred at 80° C. overnight. The mixture was cooled down to roomtemperature, and the solid was removed by filtration.(4-fluorophenyl)methanamine (500 mg, 4.0 mmol) and 1 mL DMF were added.The resulting mixture as stirred at the same temperature for 1 h. Thesolvent was removed and the residue was taken up by ethyl acetate,washed with saturated NH₄Cl aqueous solution and brine. The organicsolution was dried over anhydrous MgSO₄, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(eluting with 15% ethyl acetate in petroleum) to give the desiredproduct (280 mg, 45% yield). ESI-MS m/z: 621.

5-((4-fluorobenzylamino)methyl)-3-bromo-1-trityl-1H-indazol-6-amine

To a solution ofN-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)(4-fluorophenyl)methanamine(280 mg, 0.45 mmol) in 6 mL of 1:5 mixture of AcOH/2-PrOH, was added Zndust (587 mg, 9.0 mmol). The reaction mixture was stirred at 60° C. for1 h. The reaction mixture was cooled to room temperature. Solid wasremoved by filtration and the filtrate was concentrated in vacuo. Theresidue was dissolved in ethyl acetate, and washed with water. Theorganic phase was washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give the desired crudeproduct as a yellow solid (230 mg). ESI-MS m/z: 591.

6-(4-fluorobenzyl)-3-bromo-5,6-dihydro-1-trityl-1H-pyrazol[4,3-g]quinazolin-7(8H)-one

To a solution of5-((4-fluorobenzylamino)methyl)-3-bromo-1-trityl-1H-indazol-6-amine (230mg, 0.39 mmol) in 6 mL of DCM, Et₃N (433 mg, 4.3 mmol) was addedfollowed by CDI (316 mg, 1.95 mmol). The reaction mixture was stirred atroom temperature overnight. The mixture was concentrated in vacuo andthe residue was purified by silica gel column (eluting with 40% ethylacetate in petroleum) to give the desired product (180 mg, 75% yieldover 2 steps). ESI-MS m/z: 617.

6-(4-fluorobenzyl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

To a solution of6-(4-fluorobenzyl)-3-bromo-5,6-dihydro-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(135 mg, 0.22 mmol) and pyridin-4-ylboronic acid (60 mg, 0.44 mmol) in11 mL of 10:1 mixture of dioxane and water at room temperature,PdCl₂(dppf) (16 mg, 0.02 mmol) and K₂CO₃ (91 mg, 0.66 mmol) were added.The reaction mixture was degassed and backfilled with nitrogen. Thereaction mixture was stirred at 80° C. overnight. The solvent wasremoved and the residue was purified by silica gel column chromatography(eluting with 40% ethyl acetate in petroleum) to give the desiredproduct (22 mg, 16% yield). ESI-MS m/z: 630.

6-(4-fluorobenzyl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

To a solution of6-(4-fluorobenzyl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(22 mg, 0.03 mmol) in 3 mL of DCM, was added 3 mL of TFA, and themixture was stirred at RT for 2 h. The solvent was removed, and NH₃.MeOHwas added to adjust the pH >8.0. The resulting mixture was concentratedin vacuo and the residue was purified by silica gel columnchromatography (eluting with 7% MeOH in DCM) to give the desired product(3 mg, 22% yield). ¹H NMR (400 MHz, DMSO-d6) δ: 13.21 (br, 1H), 9.62 (s,1H), 8.50 (d, J=5.2 Hz, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.74 (d, J=4.4Hz, 1H), 7.41 (dd, J=5.6, 8.0 Hz, 2H), 7.22 (t, J=8.8 Hz, 2H), 6.97 (s,1H), 4.58 (s, 2H), 4.45 (s, 2H), 2.55 (s, 3H). ESI-MS m/z: 388.

Example 4: Synthesis of5,6-dihydro-3-(2-methylpyridin-4-yl)-6-((thiazol-4-yl)methyl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one2-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)isoindoline-1,3-dione

To a solution of 3-bromo-5-methyl-6-nitro-1-trityl-1H-indazole (4.0 g,8.0 mmol) and NBS (2.14 mg, 12.0 mmol) in 40 mL of CCl₄ at roomtemperature, AIBN (787 mg, 4.8 mmol) was added. The reaction mixture wasstirred at 80° C. overnight. The mixture was cooled down to roomtemperature and the solid was removed by filtration. The solvent wasremoved by vacuum, n-potassiophthalimide (4.44 g, 24 mmol) and 40 mL ofDMF were added. The resulting mixture was stirred at the sametemperature for 1 h. The solvent was removed and the residue was takenup by ethyl acetate, washed with water and brine. The organic solutionwas dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (eluting with15% ethyl acetate in petroleum) to give the desired product (2.3 g, 45%yield). ESI-MS m/z: 645

(3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methanamine

To a solution of2-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)isoindoline-1,3-dione(300 mg, 0.47 mmol) in methanol (6 mL), was added hydrazinehydrate (233mg, 4.7 mmol), and the reaction was stirred at 70° C. for 2 h. Thereaction mixture was cooled down to room temperature, and the solid wasremoved by filtration. The filtrate was concentrated in vacuo and theresidue was purified by silica gel column chromatography (eluting with50% ethyl acetate in petroleum) to give the desired product (140 mg, 58%yield). ESI-MS m/z: 515

N-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)(thiazol-4-yl)methanamine

To a mixture of (3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methanamine(380 mg, 0.74 mmol) and thiazole-4-carbaldehyde (84 mg, 0.74 mmol), wasadded 3 drops of acetic acid, and the resulting mixture was stirred atroom temperature for 1 hour. Sodium cyanoborohydride (93 mg, 1.48 mmol)was added to the reaction. The reaction mixture was stirred at roomtemperature overnight. The mixture was concentrated in vacuo, and theresidue was purified by silica silca gel column chromatography (elutingwith 25% ethyl acetate in dichloromethane) to give the desired product(177 mg, 32% yield). ESI-MS m/z: 612.

5-(((thiazol-4-yl)methylamino)methyl)-3-bromo-1-trityl-1H-indazol-6-amine

To a solution ofN-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)(thiazol-4-yl)methanamine(177 mg, 0.29 mmol) in 12 mL of 1:5 mixture of AcOH/2-PrOH, was added Zndust (378 mg, 5.8 mmol). The reaction mixture was stirred at 60° C. for1 h. The reaction mixture was cooled to room temperature. Solid wasremoved by filtration and the filtrate was concentrated in vacuo. Theresidue was dissolved in ethyl acetate, and then washed with water. Theorganic phase was collected, washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to give the desiredcrude product as a yellow solid (158 mg). ESI-MS m/z: 582.

5-(((thiazol-4-yl)methylamino)methyl)-3-bromo-1-trityl-1H-indazol-6-amine

To a solution of5-(((thiazol-4-yl)methylamino)methyl)-3-bromo-1-trityl-1H-indazol-6-amine(158 mg, 0.27 mmol) in 8 mL of DCM, Et₃N (303 mg, 43.0 mmol) was addedfollowed by CDI (221 mg, 1.36 mmol). The reaction mixture was stirred atroom temperature overnight. The mixture was concentrated in vacuo andthe residue was purified by silica gel column (eluting with 4% methanolin dichloromethane) to give the desired product (65 mg, 39% yield over 2steps). ESI-MS m/z: 606.

5,6-dihydro-3-(2-methylpyridin-4-yl)-6-((thiazol-4-yl)methyl)-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

To a solution of5-(((thiazol-4-yl)methylamino)methyl)-3-bromo-1-trityl-1H-indazol-6-amine(65 mg, 0.11 mmol) and pyridin-4-ylboronic acid (29 mg, 0.21 mmol) in 11mL of 10:1 mixture of dioxane and water at room temperature, PdCl₂(dppf)(23 mg, 0.03 mmol) and K₂CO₃ (45 mg, 0.33 mmol) were added. The reactionmixture was degassed and backfilled with nitrogen. The reaction mixturewas stirred at 80° C. overnight. The solvent was removed and the residuewas purified by silica gel column chromatography (eluting with 2.5%dichloromethane in methanol) to give the desired product (38 mg, 57%yield). ESI-MS m/z: 630.

5,6-dihydro-3-(2-methylpyridin-4-yl)-6-((thiazol-4-yl)methyl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

To a solution of5,6-dihydro-3-(2-methylpyridin-4-yl)-6-((thiazol-4-yl)methyl)-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(38 mg, 0.06 mmol) in 3 mL of DCM, was added 3 mL of TFA, and theresulting mixture was stirred at RT for 2 h. The solvent was removed,NH₃.MeOH was added to adjust the pH >8.0. The resulting mixture wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (eluting with 7% MeOH in DCM) to give the desired product(15 mg, 64% yield). ¹H NMR (400 MHz, DMSO-d6) δ: 13.24 (br, 1H), 9.60(s, 1H), 9.10 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 7.99 (s, 1H),7.82 (s, 1H), 7.76 (s, 1H), 7.57 (s, 1H), 6.69 (s, 1H), 4.72 (s, 2H),4.60 (s, 2H), 2.56 (s, 3H). ESI-MS m/z: 376.

Example 5:5,6-dihydro-3-(2-methoxypyrimidin-5-yl)-6-((R)-1-((thiophen-2-yl)methyl)piperidin-3-yl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one3-bromo-5-(bromomethyl)-6-nitro-1-trityl-1H-indazole

The mixture of 3-bromo-5-methyl-6-nitro-1-trityl-1H-indazole (2 g, 4mmol), NBS (1 g, 5.6 mmol) and AIBN (400 mg, 2.4 mmol) in 40 mL of CCl₄was stirred at 80° C. overnight. The reaction mixture was concentratedin vacuo to give the desired product (2.5 g) as a brown solid, which wasused in the next step without further purification.

(R)-tert-butyl3-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methylamino)piperidine-1-carboxylate

The mixture of 3-bromo-5-(bromomethyl)-6-nitro-1-trityl-1H-indazole (2.5g, 4.3 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (2.5 g,12.9 mmol) in 30 mL of THF was stirred at RT for 16 h. The mixture wasconcentrated in vacuo and the residue was purified by silica gel column(0-20% EA in PE) to afford the desired product (860 mg, 47.8% yield) asan orange oil.

(R)-tert-butyl3-((6-amino-3-bromo-1-trityl-1H-indazol-5-yl)methylamino)piperidine-1-carboxylate

The mixture of3-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methylamino)piperidine-1-carboxylate(860 mg, 1.23 mmol) in 10 mL of 4:1 mixture of HOAc and IPA at 60° C.was stirred for 1 h. To this mixture, Zn (1.6 g, 24.7 mmol) was added.The reaction mixture was stirred at 60° C. for 1 h. Solvent was removedand the residue was taken with ethyl acetate. The mixture was filteredthrough a pad of Celite and the filtrate was washed with brine. Theorganic solution was dried over anhydrous MgSO₄, filtered and and theresidue was concentrated in vacuo to give the desired product (668 mg,81% yield). ESI-MS m/z: 668.

(R)-tert-butyl3-(3-bromo-7,8-dihydro-7-oxo-1-trityl-1H-pyrazolo[4,3-g]quinazolin-6(5H)-yl)piperidine-1-carboxylate

The mixture of (R)-tert-butyl3-((6-amino-3-bromo-1-trityl-1H-indazol-5-yl)methylamino)piperidine-1-carboxylate(668 mg, 1 mmol), CDI (890 mg, 5.5 mmol) and Et₃N (1.1 g, 11 mmol) in 10mL of DCM was stirred at RT for 16 h. Solvent was removed and theresidue was taken up by ethyl acetate, and washed with brine. Theorganic solution was dried over anhydrous MgSO₄, filtered and andconcentrated in vacuo. The residue was purified by silica column (0-30%EA in PE) to afford the desired product (400 mg, 58% yield) as a yellowsolid. ESI-MS m/z: 692.

(R)-tert-butyl3-(7,8-dihydro-3-(2-methoxypyrimidin-5-yl)-7-oxo-1-trityl-1H-pyrazolo[4,3-g]quinazolin-6(5H)-yl)piperidine-1-carboxylate

The mixture of (R)-tert-butyl3-(3-bromo-7,8-dihydro-7-oxo-1-trityl-1H-pyrazolo[4,3-g]quinazolin-6(5H)-yl)piperidine-1-carboxylate(400 mg, 0.56 mmol), 2-methoxypyrimidin-5-yl-5-boronic acid (250 mg,1.65 mmol), Pd(dppf)Cl₂ (81 mg, 0.1 mmol) and K₂CO₃ (138 mg, 1 mmol) in18 mL of 1:5 H₂O/dioxane was stirred at 100° C. for 16 h. Solvent wasremoved and the residue was taken up by ethyl acetate, and washed withbrine. The organic solution was dried over anhydrous MgSO₄, filtered andand concentrated in vacuo. The residue was purified by silica gel column(0-50% EA in PE) to afford the desired product (270 mg, 75% yield) as alight yellow solid. ESI-MS m/z: 722.

5,6-dihydro-3-(2-methoxypyrimidin-5-yl)-6-((R)-piperidin-3-yl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

The mixture of (R)-tert-butyl3-(7,8-dihydro-3-(2-methoxypyrimidin-5-yl)-7-oxo-1-trityl-1H-pyrazolo[4,3-g]quinazolin-6(5H)-yl)piperidine-1-carboxylate(270 mg, 0.37 mmol) and 3 mL of TFA and 7 mL of DCM. The reactionmixture was stirred at room temperature for 16 h. The mixture wasconcentrated in vacuo and the residue was purified by silica gel column(0-20% MeOH in DCM) to afford the desired product (130 mg, 92.8% yield)as a white solid. ESI-MS m/z: 380.

5,6-dihydro-3-(2-methoxypyrimidin-5-yl)-6-((R)-1-((thiophen-2-yl)methyl)piperidin-3-yl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

The mixture of5,6-dihydro-3-(2-methoxypyrimidin-5-yl)-6-((R)-piperidin-3-yl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(130 mg, 0.34 mmol) and thiophene-2-carbaldehyde (307 mg, 2.74 mmol) in70 mL of 8:1 mixture of HOAc and MeOH was stirred at room temperaturefor 1 h. NaBH₃CN (55 mg, 0.86 mmol) was added and the resulting mixturewas stirred at room temperature for 16 h. The reaction mixture wasconcentrated in vacuo and the residue was purified by silica gel column(0-10% MeOH in DCM) to afford the desired product (110 mg, 67.5% yield)as a light yellow solid. ¹HNMR (400 MHz, DMSO-d6) δ: 13.05 (s, 1H), 9.45(s, 1H), 9.14 (s, 2H), 7.94 (s, 1H), 7.42-7.41 (m, 1H), 6.96-6.91 (m,3H), 4.5494.37 (m, 2H), 4.30-4.23 (m, 1H), 4.00 (s, 3H), 3.72-3.71 (m,2H), 2.86-2.27 (m, 2H), 2.19-2.14 (m, 1H), 1.91-1.87 (m, 1H), 1.75-1.50(m, 4H). ESI-MS m/z: 476.

Example 6: Synthesis of3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinolin-7(8H)-one6-amino-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carbaldehyde

To a stirred solution ofN-(5-formyl-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)acetamide(16.0 g, 28 mmol) in 200 mL of dry MeOH at ° C., SOCl₂ (12 ml) was addeddropwise. The reaction mixture was stirred at room temperatureovernight. The solvent was removed. The residue was diluted with ethylacetate, and washed with saturated NaHCO₃ aqueous solution. The organicsolution was dried over anhydrous MgSO₄, filtered and concentrated invacuo to give of the desired product (15 g) as a brown solid, which wasused in the next step without further purification.

N-(5-formyl-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)-3-phenylbutanamide

To a stirred solution of6-amino-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carbaldehyde(1.5 g, 3.1 mmol) in 20 mL of dry DCM at 0° C., TEA (1.5 g, 13.7 mmol)was added followed by slow addition of 3-phenylbutanoyl chloride (1.6 g,9.1 mmol). The reaction mixture was stirred at the same temperature for4 h. The solvent was removed, and the residue was purified via silicagel column chromatography (eluting with DCM/MeOH=25:1) to afford thedesired product (2.0 g, 95% yield) as a yellow solid.

3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

Condition 1:

To a solution ofN-(5-formyl-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)-3-phenylbutanamide(2.0 g, 3.1 mmol) in 60 mL of THF at room temperature, KOH (700 mg, 12.5mmol) and 1 mL of EtOH were added. The reaction mixture was degassed andbackfilled with nitrogen. The reaction mixture was stirred at 40° C.overnight. The solvent was removed and the residue was purified viasilica gel column chromatography (eluting with EA/PE=1:2) to give thedesired product (50 mg, 3% yield). ESI-MS m/z: 623.

Condition 2:

To a solution ofN-(5-formyl-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)-3-phenylbutanamide(7.0 g, 10.9 mmol) in 200 mL of MeOH, MeONa (5.5 g, 100 mmol) was added.The reaction mixture was degassed and backfilled with nitrogen. Thereaction mixture was stirred at reflux overnight. The solvent wasremoved and the residue was purified via silica gel columnchromatography (eluting with EA/PE=1:2) to give the desired product (1.3g, 18% yield). ESI-MS m/z: 623.

3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

To a solution of3-(2-methylpyridin-4-yl)-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(1.3 g, 2.0 mmol) in 4 mL of DCM, 4 mL of TFA was added. The reactionwas stirred at room temperature for 1 h. The solvent was removed and theresidue was quenched by 7M NH₃.MeOH. The solvent was removed and theresidue was purified via silica gel column chromatography (eluting withDCM/MeOH=20:1) to give the desired product (500 mg, 66% yield). ¹H NMR(400 MHz, DMSO-d6) δ: 13.44 (br, 1H), 11.67 (s, 1H), 8.62 (s, 1H), 8.56(d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.86 (d, J=5.2 Hz, 1H),7.38 (s, 1H), 7.15-7.35 (m, 5H), 4.38 (q, J=7.2 Hz, 1H), 2.61 (s, 3H),1.56 (q, J=7.2 Hz, 3H). ESI-MS m/z: 381.

Example 7: Synthesis of3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl acetate

To a stirred solution of3-bromo-5-(bromomethyl)-6-nitro-1-trityl-1H-indazole (500 mg, 1 mmol,not pure) in 10 mL of dry DMF, AcOK (700 mg, 7 mmol) was added. Thereaction mixture was stirred at room temperature for 3 h. The reactionwas partitioned between EA and H₂O. The organic layer was concentratedin vacuo and the residue was purified via silica gel columnchromatography (eluting with EA/PE=1:6) to afford the desired product(250 mg, 50% yield) as a yellow solid.

(6-amino-3-bromo-1-trityl-1H-indazol-5-yl)methyl acetate

To a stirred solution of(3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl acetate (500 mg, 1mmol) in 10 mL of EtOH, Na₂SO₄ (1.7 g, 10 mmol) was added. The reactionmixture was stirred at reflux for 10 h. The solvent was removed, and theresidue was partitioned between EA and H₂O. The organic layer wasconcentrated in vacuo to afford the product (350 mg, 70% yield) as ayellow solid without further purification.

(6-amino-3-bromo-1-trityl-1H-indazol-5-yl)methanol

To a solution of (6-amino-3-bromo-1-trityl-1H-indazol-5-yl)methylacetate (350 mg, 0.65 mmol) in a mixture THF/EtOH/H₂O (6.0 mL, 1:1:1) atroom temperature, LiOH (109 mg, 2.61 mmol) was added. The reactionmixture was stirred for 8 h. The solvent was removed and the residue waspurified via silica gel column chromatography (eluting with EA/PE=1:3)to give the product (130 mg, 50% yield) as a yellow solid.

6-amino-3-bromo-1-trityl-1H-indazole-5-carbaldehyde

To a stirred solution of(6-amino-3-bromo-1-trityl-1H-indazol-5-yl)methanol (130 mg, 0.27 mmol)in 10 mL of DCM, MnO₂ (480 mg, 5.4 mmol) was added. The reaction mixturewas stirred at room temperature for 10 h. The solid was removed byfiltration and the filtrate was concentrated in vacuo to afford theproduct (100 mg, 70% yield) as a yellow solid without furtherpurification.

3-bromo-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

To a solution ofN-(3-bromo-5-formyl-1-trityl-1H-indazol-6-yl)-3-phenylbutanamide (2.0 g,3.2 mmol) in 40 mL of MeOH, MeONa (1.73 g, 32 mmol) was added. Thereaction mixture was degassed and backfilled with nitrogen. The reactionmixture was stirred at reflux overnight. The solvent was removed and theresidue was purified via silica gel column chromatography (eluting withEA/PE=1:5) to give the desired product (300 mg, 15% yield). Some of thestarting material (about 1.0 g) was recovered. ESI-MS m/z: 612.

3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

The mixture of3-bromo-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(200 mg, 0.33 mmol), K₂CO₃ (100 mg, 0.72 mmol) and 1-methylpiperazine(0.5 mL) in 2 mL of DMSO was stirred at 100° C. in a sealed tube for 10h. The residue was purified via silica gel column chromatography(eluting with EA/PE=1:2) to give the desired product (70 mg, 30% yield).ESI-MS m/z: 707.

3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-(1-phenylethyl)-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

To a solution of3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-(1-phenylethyl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(70 mg, 0.1 mmol) in 2 mL of DCM, 2 mL of TFA was added. The reactionmixture was stirred at room temperature for 1 h. The solvent was removedand the residue was quenched by 7M NH₃.MeOH. The solvent was removed andthe residue was purified via silica gel column chromatography (elutingwith DCM/MeOH=20:1) to give the desired product (10 mg, 66% yield). ¹HNMR (400 MHz, DMSO-d6) δ: 13.02 (br, 1H), 11.59 (br, 1H), 8.82 (d, J=2.0Hz, 1H), 8.47 (s, 1H), 8.56 (dd, J=8.8, 2.0 Hz 1H), 7.99 (s, 1H), 7.29(m, 5H), 7.18 (m, 1H), 6.98 (d, J=8.8 Hz, 1H), 4.37 (q, J=7.2 Hz, 1H),3.60 (m, 4H), 2.51 (m, 3H), 2.46 (m, 4H), 1.54 (d, J=7.2 Hz, 3H). ESI-MSm/z: 465.

Example 8: Synthesis of6-(4-tert-butyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one3,3-dimethyl-1-nitrobutan-2-ol

To a mixture of pivalaldehyde (10 g, 116 mmol) and nitromethane (7.1 mg,116 mmol) in 150 mL of methanol in an ice-bath, sodium hydroxide aqueous(4.88 g, 122 mmol, 88 ml H₂O) was added slowly and the temperature wasallowed to rise slowly to RT. The mixture was stirred for 1 h. Thesolvent was removed, and the residue was dissolved in water and ethylacetate. The mixture was washed with a solution of sodium carbonate. Theorganic phase was separated, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give the desired product as ayellow oil (14 g, 82% yield). ESI-MS m/z: 148

(E)-3,3-dimethyl-1-nitrobut-1-ene

To a solution of 3,3-dimethyl-1-nitrobutan-2-ol (4.0 g, 27 mmol) in 20mL of dichloromethane at 0° C., trifluoroacetic anhydride (3.5 g, 16.5mmol) was slowly added followed by triethylamine and the temperature wasallowed to rise slowly to room temperate. The mixture was stirred at RTfor 3 h. The reaction mixture was filtered through a pad of silica geland rinsed with dichloromethane. The filtrate was concentrated (noheating) in vacuo to give a yellow oil. The oil was taken up in 20%petroleum in ether, filtered through a pad of silica gel and rinsed with20% petroleum in ether. The filtrate was concentrated (no heating) invacuo to give the product as a yellow oil (3 g crude product). ESI-MSm/z: 130.

3-tert-butyl-1-benzyl-4-nitropyrrolidine

To a mixture of (E)-3,3-dimethyl-1-nitrobut-1-ene (3.5 g, 27 mmol) andTFA (307 mg, 2.7 mmol) in 300 mL of dichloromethane,N-(methoxymethyl)-N-((trimethylsilyl)methyl)(phenyl)methanamine (7.7 g,32 mmol) was slowly added and the resulting mixture was stirred at roomtemperature over weekend. The solvent was removed and the residue waspurified by silica gel column chromatography (eluting with 2-2.5% ethylacetate in petroleum) to give the desired product as a yellow oil (2.3g, 32% yield). ESI-MS m/z: 263.

4-tert-butyl-1-benzylpyrrolidin-3-amine

To a mixture of 3-tert-butyl-1-benzyl-4-nitropyrrolidine (1.2 g, 4.6mmol) in 20 mL of methanol at 0° C., Ranney Ni (1 g) was added and theresulting mixture was stirred at room temperature for 1 h. The solid wasremoved by filtration and the filtrate was concentrated in vacuo to givethe product as a yellow oil (2.3 g, 32% yield). ESI-MS m/z: 233.

4-tert-butyl-1-benzyl-N-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)pyrrolidin-3-aminewas synthesized by general scheme D.

5-((4-tert-butyl-1-benzylpyrrolidin-3-ylamino)methyl)-3-bromo-1-trityl-1H-indazol-6-aminewas synthesized by general scheme D.

6-(4-tert-butyl-1-benzylpyrrolidin-3-yl)-3-bromo-5,6-dihydro-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-onewas synthesized by general scheme D.

6-(4-tert-butyl-1-benzylpyrrolidin-3-yl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-onewas synthesized by general scheme D.

Tert-butyl3-tert-butyl-4-(7,8-dihydro-3-(2-methylpyridin-4-yl)-7-oxo-1-trityl-1Hpyrazolo[4,3-g]quinazolin-6(5H)-yl)pyrrolidine-1-carboxylate

A mixture of6-(4-tert-butyl-1-benzylpyrrolidin-3-yl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(200 mg, 0.27 mmol), (Boc)₂O (190 mg, 0.81 mmol) and 10% Pd(OH)₂/C (50mg) in 20 mL of ethyl acetate was stirred under H₂ atmosphere at roomtemperature overnight. The solid was removed by filtration and thefiltrate was concentrated in vacuo. The residue was purified by silicagel column chromatography (eluting with 50% ethyl acetate in petroleum)to give the desired product as a yellow solid (60 mg, 30% yield). ESI-MSm/z: 747.

6-(4-tert-butylpyrrolidin-3-yl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1-trityl-1Hpyrazolo[4,3-g]quinazolin-7(8H)-one

A solution of tert-butyl3-tert-butyl-4-(7,8-dihydro-3-(2-methylpyridin-4-yl)-7-oxo-1-trityl-1H-pyrazolo[4,3-g]quinazolin-6(5H)-yl)pyrrolidine-1-carboxylate(60 mg, 0.08 mmol) in AcOH/MeOH (1:4, 6 mL) was stirred at roomtemperature for 1.5 h. To this mixture, NH₃.MeOH was added to adjust thepH to >8.0. The mixture was concentrated in vacuo and the residue waspurified by silica gel column chromatography (eluting with 8% NH₃.MeOHin dichloromethane) to give the desired product as a yellow solid (30mg, 58% yield). ESI-MS m/z: 647.

6-(4-tert-butyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

To a solution of6-(4-tert-butylpyrrolidin-3-yl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one(30 mg, 0.05 mmol) in DMF was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (22 mg, 0.09 mmol) followed byN-ethyl-N-isopropylpropan-2-amine (24 mg, 0.18 mmol). The mixture wasstirred at room temperature overnight. The mixture was partitionedbetween water and ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (elutingwith 5% methanol in dichloromethane) to give the desired product as ayellow solid. (30 mg, 89% yield). ESI-MS m/z: 729.

6-(4-tert-butyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-g]quinazolin-7(8H)-one

was synthesized by general scheme D.

(10 mg, 50% yield). ¹H NMR (400 MHz, DMSO-d6) δ: 13.22 (br, 1H), 9.47(s, 1H), 8.54 (d, J=4.8 Hz, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.79 (d,J=5.2 Hz, 1H), 6.96 (s, 1H), 4.91 (m, 2H), 4.65 (d, J=12.3 MHz, 1H),4.51 (d, J=12.3 Hz, 1H), 3.34 (m, 1H), 3.20 (m, 1H), 3.02 (m, 1H), 2.91(m, 1H), 2.73 (m, 1H), 2.58 (s, 3H), 0.85 (s, 9H). ESI-MS m/z: 487.

Example 9: Synthesis of6-(3-chlorobenzyl)-6,7-dihydro-3-(2-methoxypyrimidin-5-yl)-[1,4]diazepino[6,5-f]indazol-8(1H,5H,9H)-one3-bromo-5-(bromomethyl)-6-nitro-1-trityl-1H-indazole

To a stirred solution of 3-bromo-5-methyl-6-nitro-1-trityl-1H-indazole(5.0 g, 10 mmol) in 150 mL of CCl₄, NBS (2.7 g, 15 mmol) and AIBN (1.0g, 6.0 mmol) were added. The mixture was stirred at 80° C. overnight.The mixture was filtered and the filtrate was concentrated in vacuo. Theresidue was used in the next step without further purification.

N-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)(3-chlorophenyl)methanamine

The mixture of 3-bromo-5-(bromomethyl)-6-nitro-1-trityl-1H-indazole (4.0g, 8 mmol), (3-chlorophenyl)methanamine (7.0 g, 50 mmol) and TEA (5.0 g,50 mmol) in 150 mL of CCl₄ was stirred at 70° C. for 3 h. The mixturewas washed with water and concentrated in vacuo. The residue waspurified by silica gel column (0-2% methanol in dichloromethane) toafford the desired product (1.6 g, 25% yield) as a yellow solid. ESI-MSm/z: 639.

Ethyl2-(N-(3-chlorobenzyl)-N-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)amino)acetate

The mixture ofN-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)(3-chlorophenyl)methanamine(1.6 g, 2.5 mmol) and NaOH (150 mg, 3.76 mmol) in 10 mL of DMF wasstirred at RT for 30 min. Ethyl 2-bromoacetate (630 mg, 3.76 mmol) wasadded to the mixture and the resulting mixture was stirred at 90° C. for3 h. The mixture was cooled down, poured into water and extracted withEA (100 mL×3). The organic layer was concentrated in vacuo and theresidue was purified by silica gel column (0-1% methanol indichloromethane) to give the desired product (1.2 g, 67% yield). ESI-MSm/z: 725.

6-(3-chlorobenzyl)-3-bromo-6,7-dihydro-1-trityl-[1,4]diazepino[6,5-f]indazol-8(1H,5H,9H)-one

To a solution of ethyl2-(N-(3-chlorobenzyl)-N-((3-bromo-6-nitro-1-trityl-1H-indazol-5-yl)methyl)amino)acetate(1.1 g, 1.52 mmol) in AcOH/i-PrOH (20 mL/4 mL) at 60° C., Zn (2.0 g,30.3 mmol) was added and the resulting mixture was stirred at 60° C. for5 h. The mixture was concentrated in vacuo. The residue was diluted withEA and washed with saturated NaHCO₃. The organic layer was concentratedin vacuo and the residue was purified by silica gel column (0-2%methanol in dichloromethane) to give the desired product (910 mg, 93%yield). ESI-MS m/z: 649.

6-(3-chlorobenzyl)-6,7-dihydro-3-(2-methoxypyrimidin-5-yl)-1-trityl-[1,4]diazepino[6,5-f]indazol-8(1H,5H,9H)-one

The mixture of6-(3-chlorobenzyl)-3-bromo-6,7-dihydro-1-trityl-[1,4]diazepino[6,5-f]indazol-8(1H,5H,9H)-one(400 mg, 0.62 mmol), 2-methoxypyrimidin-5-yl-5-boronic acid (240 mg,1.54 mmol), Pd(dppf)Cl₂ and K₂CO₃ in dioxane/H₂O (15 mL/1.5 mL) wasstirred at 90° C. overnight. The mixture was concentrated in vacuo andthe residue was purified by silica gel column (0-1% methanol indichloromethane) to give the desired product (320 mg, 76% yield). ESI-MSm/z: 677.

6-(3-chlorobenzyl)-6,7-dihydro-3-(2-methoxypyrimidin-5-yl)-[1,4]diazepino[6,5-f]indazol-8(1H,5H,9H)-one

To a solution of6-(3-chlorobenzyl)-6,7-dihydro-3-(2-methoxypyrimidin-5-yl)-1-trityl-[1,4]diazepino[6,5-f]indazol-8(1H,5H,9H)-one(100 mg, 0.147 mmol) in 3 mL of DCM was added TFA (6 mL). The mixturewas stirred at RT for 1 h. The mixture was concentrated in vacuo, anddiluted with NH₃ in methanol. The mixture was concentrated in vacuo andthe residue was purified by silica gel column (0-10% methanol indichloromethane) to give the desired product (25 mg, 39% yield). ¹H NMR(400 MHz, DMSO-d6) δ: 13.34 (s, 1H), 10.25 (s, 1H), 9.21 (m, 2H), 8.09(s, 1H), 7.34-7.41 (m, 4H), 7.23 (s, 1H), 4.00 (s, 3H) 3.83 (s, 2H),3.75 (s, 2H), 3.12 (s, 2H). ESI-MS m/z: 435.

Example 10: Synthesis of7-(4-fluorobenzyl)-67-dihydro-3-(2-methoxypyrimidin-5-yl)-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one5-bromo-6-nitro-1-trityl-1H-indazole

To a stirred solution of 5-bromo-6-nitro-1H-indazole (5 g, 20.7 mmol) in60 mL of dry THF at 0° C., NaH (60% in mineral oil, 1.16 g, 29 mmol) wasadded and the reaction mixture was stirred at the same temperature for30 min. TrtCl (6.92 g, 24.8 mmol) was added to the mixture. The reactionmixture was stirred at room temperature for for 6 h. Solvent wasremoved. The residue was dissolved in ethyl acetate and washed withbrine. The organic solution was dried over anhydrous MgSO₄, filtered andand concentrated in vacuo. The residue was purified by silica gel columnto afford the desired product (9 g, 90% yield) as a yellow solid.

6-nitro-1-trityl-5-vinyl-1H-indazole

To a mixture of 5-bromo-6-nitro-1-trityl-1H-indazole (9 g, 18.6 mmol)and Pd(pph₃)₄ (2.15 g, 1.86 mmol) in toluene (60 mL), Tributyl(vinyl)tin(7 g, 22.32 mmol) was added. The resulting mixture was degassed andback-filled with argon three times and then stirred at 115° C. for 4 h.The mixture was allowed to cool to room temperature. The solution waspoured into water (100 mL) and extracted with EA (300 mL) three times.The organic layer was washed with brine two times, dried over Na₂SO₄,and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel to afford the desired product6-nitro-1-trityl-5-vinyl-1H-indazole (6.8 g, 85% yield) as a whitesolid.

2-(6-nitro-1-trityl-1H-indazol-5-yl)ethanol

To a stirred solution of 6-nitro-1-trityl-5-vinyl-1H-indazole (6.8 g,15.77 mmol) in 60 mL of dry THF at 0° C., BH₃.THF (1N, 47.33 mL, 47.33mmol) was slowly added and the reaction mixture was stirred at RT for 5h. To this mixture, NaOH (3N, 15.77 mL, 47.33 mmol) and H₂O₂ (4.94 g,47.33 mmol, 30%) were slowly added and the resulting mixture was stirredat RT for 5 h. The solution was poured into water (100 mL) and extractedwith EA (100 mL) three times. The organic layer was washed with brinetwo times, dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by silica gel to afford the desired product2-(6-nitro-1-trityl-1H-indazol-5-yl)ethanol (3.9 g, 55% yield).

2-(6-nitro-1-trityl-1H-indazol-5-yl)acetic acid

The mixture of H₅IO₆ (4.94 g, 21.69 mmol) and CrO₃ (43 mg, 0.43 mmol) in50 mL of CH₃CN:H₂O (99.25%:0.75%) was stirred at RT for 2 h. To thismixture, 2-(6-nitro-1-trityl-1H-indazol-5-yl)ethanol (3.9 g, 8.67 mmol)in 50 mL of CH₃CN:H₂O (99.25%: 0.75%) was slowly added and the reactionmixture was stirred at RT for 3 h. The solution was poured into water(100 mL) and extracted with EA (100 mL) three times. The organic layerwas washed with brine two times, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel to afford the desiredproduct 2-(6-nitro-1-trityl-1H-indazol-5-yl)acetic acid (3.2 g, 80%yield).

N-(4-fluorobenzyl)-2-(6-nitro-1-trityl-1H-indazol-5-yl)acetamide

To a stirred solution of 2-(6-nitro-1-trityl-1H-indazol-5-yl)acetic acid(3.2 g, 6.91 mmol) in 40 mL of dry DMF, (4-fluorophenyl)methanamine(1.04 g, 8.29 mmol), EDC.HCl (2.64 g, 13.82 mmol), HOBt (1.86 g, 13.82mmol) and TEA (2.79 g, 27.64 mmol) were added and the reaction mixturewas stirred at RT overnight. The solution was poured into water (100 mL)and extracted with EA (100 mL) three times. The organic layer was washedwith brine two times, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by silica gel column to afford the desired productN-(4-fluorobenzyl)-2-(6-nitro-1-trityl-1H-indazol-5-yl)acetamide (3.15g, 80% yield).

N-(4-fluorobenzyl)-2-(6-nitro-1-trityl-1H-indazol-5-yl)ethanamine

To a stirred solution ofN-(4-fluorobenzyl)-2-(6-nitro-1-trityl-1H-indazol-5-yl)acetamide (3.15g, 5.53 mmol) in 30 mL of dry THF at 0° C., BH₃.THF (1 N, 16.6 mL, 16.6mmol) was slowly added and the reaction mixture was stirred at refluxfor 5 h. The solution was poured into water (80 mL) and extracted withEA (100 mL) three times. The organic layer was washed with brine twotimes, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column to afford the desired productN-(4-fluorobenzyl)-2-(6-nitro-1-trityl-1H-indazol-5-yl)ethanamine (2.31g, 75% yield).

5-(2-(4-fluorobenzylamino)ethyl)-1-trityl-1H-indazol-6-amine

To a stirred solution ofN-(4-fluorobenzyl)-2-(6-nitro-1-trityl-1H-indazol-5-yl)ethanamine (2.31g, 4.15 mmol) in 40 mL of 1:5 AcOH/2-PrOH mixture at 60° C., Zn dust(5.4 g, 83.1 mmol) was added. The reaction mixture was stirred at 60° C.for 1 h. The reaction mixture was cooled to room temperature. Solid wasremoved by filtration and the filtrate was concentrated in vacuo. Theresidue was poured into NaHCO₃ solution (80 mL) and extracted with EA(100 mL) three times. The organic layer was washed with brine two times,dried over Na₂SO₄, and concentrated in vacuo. The yellow solid5-(2-(4-fluorobenzylamino)ethyl)-1-trityl-1H-indazol-6-amine (1.96 g,90% yield) was collected which was used in the next step without furtherpurification.

7-(4-fluorobenzyl)-6,7-dihydro-1-trityl-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one

To a solution of5-(2-(4-fluorobenzylamino)ethyl)-1-trityl-1H-indazol-6-amine (1.96 g,4.56 mmol) in 20 mL of DCM, Et₃N (5 g, 50 mmol) and CDI (4 g, 25.1 mmol)were added. The reaction mixture was stirred at room temperature for 3h. The solution was poured into water (40 mL) and extracted with DCM (60mL) three times. The organic layer was washed with brine two times,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby silica gel to afford the desired product7-(4-fluorobenzyl)-6,7-dihydro-1-trityl-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one(1.51 g, 60% yield).

7-(4-fluorobenzyl)-6,7-dihydro-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one

To a solution of 7-(4-fluorobenzyl)-6,7-dihydro-1trityl-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one (1.5 g, 2.73 mmol)in 10 mL of DCM, 5 mL of TFA was added. The reaction mixture was stirredat room temperature for 5 h. Solvent was removed and the residue waspurified by prep-HPLC to give the desired product7-(4-fluorobenzyl)-6,7-dihydro-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one(677 mg, 80% yield).

7-(4-fluorobenzyl)-6,7-dihydro-3-iodo-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one

To a stirred mixture of7-(4-fluorobenzyl)-6,7-dihydro-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one(677 mg, 2.18 mmol) in DMF (10 mL) at room temperature, KOH (366 mg,6.54 mmol) was added and the resulting mixture was stirred at roomtemperature for 10 min. NIS (540 mg, 2.4 mmol,) was added to thereaction mixture. The resulting mixture was stirred at room temperaturefor 10 h. The reaction mixture was poured into water (20 mL) andextracted with ethyl acetate (60 mL×3). The combined organic layer waswashed with H₂O (200 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the desired product (713 mg, 75% yield)as a yellow solid. The crude product was used directly in the next stepwithout further purification.

Tert-butyl7-(4-fluorobenzyl)-6,7,8,9-tetrahydro-3-iodo-8-oxo-[1,3]diazepino[5,4-f]indazole-1(5H)-carboxylate

To a stirred mixture of7-(4-fluorobenzyl)-6,7-dihydro-3-iodo-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one(713 mg, 1.68 mmol) in THF (10 mL) at room temperature, (Boc)₂O (403 mg,1.85 mmol), DMAP (31 mg, 0.25 mmol), TEA (339 mg, 3.36 mmol) were added,The resulting mixture was stirred at room temperature for 10 h. Thereaction mixture was poured into water (20 mL) and extracted with ethylacetate (60 mL×3). The combined organic layer was washed with H₂O (200mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel column to afford the desiredproducttert-butyl7-(4-fluorobenzyl)-6,7,8,9-tetrahydro-3-iodo-8-oxo-[1,3]diazepino[5,4-f]indazole-1(5H)-carboxylate(720 mg, 80% yield).

7-(4-fluorobenzyl)-6,7-dihydro-3-(2-methoxypyrimidin-5-yl)-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one

To a mixture oftert-butyl7-(4-fluorobenzyl)-6,7,8,9-tetrahydro-3-iodo-8-oxo-[1,3]diazepino[5,4-f]indazole-1(5H)-carboxylate(720 mg, 1.34 mmol) and 2-methoxypyrimidin-5-yl-5-boronic acid (616 mg,4 mmol) in 1,4-dioxane/H₂O (8 mL/2 mL), PdCl₂(dppf) (292 mg, 0.4 mmol)and K₂CO₃ (553 mg, 4 mmol) were added sequentially. The resultingmixture was degassed and back-filled with argon three times and thenstirred at 85° C. for 4 h. The mixture was allowed to cool to roomtemperature. The reaction mixture was poured into water (20 mL) andextracted with ethyl acetate (60 mL×3). The combined organic layer waswashed with brine (60 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel to afford the desired product7-(4-fluorobenzyl)-6,7-dihydro-3-(2-methoxypyrimidin-5-yl)-[1,3]diazepino[5,4-f]indazol-8(1H,5H,9H)-one(392 mg, 70% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d6) δ: 13.12(s, 1H), 9.15 (s, 2H), 9.06 (s, 1H), 7.86 (s, 1H), 7.36 (m, 2H), 7.27(s, 1H), 7.17 (m, 2H), 4.54 (s, 2H), 3.99 (s, 3H), 3.42 (m, 2H), 3.08(m, 2H).

Example 11: Synthesis of5-benzyl-3-(2-methylpyridin-4-yl)imidazo[4,5-f]indazol-6(1H,5H,7H)-oneN-benzyl-6-nitro-1-trityl-1H-indazol-5-amine

The solution of 5-bromo-6-nitro-1-trityl-1H-indazole (4 g, 8.23 mmol),phenylmethanamine (1.32 g, 12.39 mmol), Pd₂(dba)₃ (760 mg, 0.823 mmol),Xantphos (480 mg, 1.24 mmol), Cs₂CO₃ (8 g, 24.49 mmol) in dioxane (30mL) was stirred at 110° C. under nitrogen overnight. The mixture wascooled to room temperature, and concentrated to dryness. The residue waspurified by flash column chromatography on silica gel (0-5% ethylacetate/petroleum ether to afford the desired product (2.16 g, 51%yield) as a red solid. ¹H NMR (400 MHz, DMSO-d6) δ: 8.08 (s, 1H), 7.70(t, J=6.0 Hz, 1H), 7.23-7.42 (m, 14H), 7.14-7.18 (m, 7H), 7.04 (s, 1H),4.51 (d, J=6.0 Hz, 2H).

N⁵-benzyl-1-trityl-1H-indazole-5,6-diamine

To the solution of N-benzyl-6-nitro-1-trityl-1H-indazol-5-amine andRaney Nickel (1 g) in THF (20 mL) and MeOH (10 mL) at 0° C. N₂H₄.H₂O (10mL) was added dropwise. The mixture was warmed to room temperature andstirred at this temperature for 1 h. The mixture was filtered, and thefiltrate was concentrated in vacuo to give the product (2 g, 97% yield)as a gray solid which was used in the next step directly.

1-benzyl-5-tritylimidazo[4,5-f]indol-2(1H,3H,5H)-one

The solution of N⁵-benzyl-1-trityl-1H-indazole-5,6-diamine (2 g, 4.17mmol), TEA (1.2 mL, 4.17 mmol) in DCM (20 mL) at 0° C., triphosgene(1.19 g, 4.17 mmol) was added slowly, and the resulting mixture wasstirred at room temperature under N₂ for 1 h. The mixture waspartitioned between water and DCM. The organic layer was dried overNa2SO4, filtered and concentrated to dryness. The residue was purifiedby flash column chromatography on silica gel (0-30% ethylacetate/petroleum ether to afford the desired product (720 mg, 34%yield).

5-benzylimidazo[4,5-f]indazol-6(1H,5H,7H)-one

The mixture of 5-benzyl-1-tritylimidazo[4,5-f]indazol-6(1H,5H,7H)-one(720 mg, 1.42 mmol) in TFA was stirred at room temperature for 1 h. Themixture was concentrated to dryness. NH3/MeOH (7 N) was added, and themixture was concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (0-10% MeOH/DCM) to afford thedesired product (358 mg, 95% yield) as a white solid.

5-benzyl-3-iodoimidazo[4,5-f]indazol-6(1H,5H,7H)-one

To the solution of 5-benzylimidazo[4,5-f]indazol-6(1H,5H,7H)-one (620mg, 2.35 mmol) in DMF (5 mL), KOH (657 mg, 11.74 mmol), was added andthe resulting mixture was stirred at room temperature for 30 min. NIS(684 mg, 3.05 mmol) was added to the mixture and then the mixture wasstirred at room temperature overnight. The mixture was partitionedbetween water and ethyl acetate. The organic layer was dried overNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby flash column chromatography on silica gel (0-10% MeOH/DCM) to affordthe desired product (358 mg, 75% yield) as a white solid.

Tert-butyl5-benzyl-3-iodo-6-oxo-6,7-dihydroimidazo[4,5-f]indazole-1(5H)-carboxylate

The mixture of 5-benzyl-3-iodoimidazo[4,5-f]indazol-6(1H,5H,7H)-one (690mg, 1.77 mmol), DMAP (108 mg, 0.88 mmol), TEA (0.5 ml, 3.54 mmol) in THF(5 mL) was stirred at room temperature for 10 min. To this mixture,BOC₂O (1.16 g, 5.3 mmol) was added, and the resulting mixture wasstirred at room temperature for 1 h. The mixture was concentrated todryness, and the residue was purified by flash column chromatography onsilica gel (0-20% ethyl acetate/petroleum ether to afford the desiredproduct (516 mg, 59% yield) as a yellow solid.

5-benzyl-3-(2-methylpyridin-4-yl)imidazo[4,5-f]indazol-6(1H,5H,7H)-one

The mixture of tert-butyl5-benzyl-3-iodo-6-oxo-6,7-dihydroimidazo[4,5-f]indazole-1(5H)-carboxylate (250 mg, 0.51 mmol), 2-methylpyridin-4-ylboronic acid(209 mg, 1.53 mmol), K₂CO₃ (209 mg, 1.53 mmol), Pd(dppf)Cl₂ (112 mg,0.15 mmol) in H₂O (3 mL) and dioxane (12 mL) was stirred at 100° C.under nitrogen overnight. The reaction mixture was concentrated todryness. The residue was purified by flash column chromatography onsilica gel (0-10% MeOH/DCM) to afford the desired product (43 mg, 24%yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ: 13.24 (s, 1H),11.08 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.75 (m, 2H), 7.63 (s, 1H), 7.36(m, 4H), 7.26 (m, 1H), 7.09 (s, 1H), 5.16 (s, 2H), 2.57 (s, 3H). ESI-MSm/z: 356.1

Example 12: Synthesis of6-(1-benzylpiperidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-g]quinolin-7(8H)-oneEthyl 4-(6-amino-3-bromo-1-trityl-1H-indazol-5-yl)but-3-enoate

To a solution of Triethyl phosphonoacetate (1.06 g, 4.73 mmol) in THF(20 mL) at 0° C., NaH (145 mg, 4.73 mmol) was added and the resultingmixture was stirred for 30 min. To this mixture,6-amino-3-bromo-1-trityl-1H-indazole-5-carbaldehyde (1.9 g, 3.94 mmol)in THF (10 mL) was added slowly and then it was stirred at RT for 1 h.The mixture was partitioned between water and EA. The organic layer wasconcentrated to dryness. The residue was purified by silica gel column(0-1.5% methanol in dichloromethane) to give the desired product (1.9 g,88% yield). ESI-MS m/z: 553.

3-bromo-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

The mixture of ethyl4-(6-amino-3-bromo-1-trityl-1H-indazol-5-yl)but-3-enoate (1.7 g, 3.08mmol) and DBU (9.35 g, 61.54 mmol) in NMP (170 mL) was stirred at 160°C. overnight. The mixture was concentrated in vacuo. The residue waspartitioned between water and EA. The organic layer was concentrated invacuo and the residue was purified by silica gel column (0-3% methanolin dichloromethane) to give the desired product (1.0 g, 64% yield).ESI-MS m/z: 506.

3-(2methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

The mixture of 3-bromo-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(1.1 g, 2.17 mmol), 2-methylpyridin-4-yl-4-boronic acid (743 mg, 5.43mmol), Pd(dppf)Cl₂ (480 mg, 0.65 mmol) and K₂CO₃ (900 mg, 6.52 mmol) indioxane/H₂O (50 mL/5 mL) was stirred at 90° C. overnight. The reactionmixture was concentrated to dryness. The residue was purified by silicagel column (0-2% methanol in dichloromethane) to give the desiredproduct (700 mg, 64% yield). ESI-MS m/z: 519.

6-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

The mixture of3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(700 mg, 1.35 mmol) and NBS (1.44 g, 8.10 mmol) in DMF (15 mL) wasstirred at 55° C. overnight. The mixture was poured into water andextracted with EA. The organic layer was concentrated to dryness. Theresidue was purified by silica gel column (DCM/MeOH=200/1-75/1) to givethe desired product (450 mg, 56% yield). ESI-MS m/z: 597.

6-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(2-methylpyridin-4-yl)-1-trityl-1Hpyrazolo[4,3-g]quinolin-7(8H)-one

The mixture of6-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(170 mg, 0.28 mmol), 1-benzyl-1,2,5,6-tetrahydropyridin-3-yl-3-boronicacid (300 mg, 1.38 mmol), Pd(dppf)Cl₂ (52 mg, 0.07 mmol) and K₂CO₃ (120mg, 0.85 mmol) in dioxane/H₂O (12 mL/3 mL) was stirred at 90° C.overnight. The reaction mixture was concentrated to dryness. The residuewas purified by silica gel column (DCM/MeOH=200/1-50/1) to give thedesired product (170 mg, 87% yield). ESI-MS m/z: 690.

Tert-butyl3-(7,8-dihydro-3-(2-methylpyridin-4-yl)-7-oxo-1-trityl-1H-pyrazolo[4,3-g]quinolin-6-yl)piperidine-1-carboxylate

The mixture of6-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(200 mg, 0.29 mmol), Pd(OH)₂/C (300 mg) and (Boc)₂O (160 mg, 0.73 mmol)in EtOAc (15 mL) was stirred under hydrogen overnight. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue waspurified by silica gel column (DCM/MeOH=200/1-50/1) to give the desiredproduct (80 mg, 40% yield). ESI-MS m/z: 702.

3-(2-methylpyridin-4-yl)-6-(piperidin-3-yl)-1H-pyrazolo[4,3-g]quinolin-7(8H)-one

To a solution of tert-butyl3-(7,8-dihydro-3-(2-methylpyridin-4-yl)-7-oxo-1-trityl-1H-pyrazolo[4,3-g]quinolin-6-yl)piperidine-1-carboxylate(75 mg, 0.107 mmol) in DCM (3 mL), was added TFA (3 ml) and Et₃SiH(3drops). The mixture was stirred at RT for 2 h. The mixture wasconcentrated in vacuo and the residue was diluted with NH₃ (inmethanol). The mixture was concentrated in vacuo and the residue (38 mg,100% yield) was used in next step without further purification. ESI-MSm/z: 360.

6-(1-benzylpiperidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-pyrazzol[4,3-g]quinolin-7(8H)-one

The mixture of3-(2-methylpyridin-4-yl)-6-(piperidin-3-yl)-1H-pyrazolo[4,3-g]quinolin-7(8H)-one(38 mg, 0.2 mmol) benzaldehyde (120 mg, 2.1 mmol) and AcOH (50 mg, 0.83mmol) in 10 mL of MeOH was stirred at RT for 2 h. To this mixture,sodium cyanoborohydride (50 mg, 0.79 mmol) was added and the resultingmixture was stirred overnight. The reaction mixture was concentrated todryness. The residue was purified by silica gel column(DCM/MeOH=100/1-10/1) to give the desired product (20 mg, 43% yield).¹HNMR (400 MHz, CD₃OD) δ: 8.70 (m, 2H), 8.44 (s, 1H), 8.39 (d, J=6.4 Hz,1H), 8.11 (s, 1H), 7.53 (s, 1H), 3.77-3.62 (m, 2H), 3.15 (m, 1H), 2.96(s, 3H), 2.85 (s, 3H), 2.21-1.95 (m, 6H). ESI-MS m/z: 450

Example 13: Synthesis of6-(3-chlorobenzyl)-3-(2-methylpyridin-4-yl)-1,8-dihydro-5H-pyrazolo[4,3-g]quinazoline-5,7(6H)-dione6-acetamido-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylicAcid

To a stirred solution ofN-(5-formyl-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazol-6-yl)acetamide(220 mg, 0.40 mmol) in 40 mL of acetone at room temperature, was added20 mL of Jones reagent. The reaction mixture was stirred at roomtemperature for 1 h. Solvent was removed and the residue was subjectedto a Flash column purification to give of the desired product (68 mg,30%).

6-amino-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxylic Acid

To a stirred solution of6-acetamido-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylicacid (268 mg, 0.50 mmol) in 10 mL of dioxane at room temperature, wasadded 10 mL of 6 N HCl. The reaction mixture was stirred at 100° C. for2 h. Solvent was removed. The residue was diluted in DCM, washed withNaHCO₃ and water. The organic layer was dried and concentrated in vacuoto give 102 mg of crude product. It was used in the next step withoutfurther purifications.

6-amino-N-(3-chlorobenzyl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide

To a stirred solution of crude6-amino-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxylic acid fromprevious step (14 mg, 0.05 mmol) and (3-chlorophenyl)methanamine (18 μL,0.15 mmol) in 2 mL of dry DMF, was added HATU (29 mg, 0.075 mmol)followed by DIEA (45 μL, 0.25 mmol). The reaction mixture was stirred atroom temperature for 2 h. The reaction mixture was diluted with ethylacetate and washed with water twice. The organic layer was dried andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel to give the desired product (11 mg, 54%) asa yellow powder.

6-(3-chlorobenzyl)-3-(2-methylpyridin-4-yl)-1,8-dihydro-5H-pyrazolo[4,3-g]quinazoline-5,7(6H)-dione

To a solution of6-amino-N-(3-chlorobenzyl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide(5 mg, 0.013 mmol) in 3 mL of DCM was added Et₃N (14 μL, 0.078 mmol)followed by CDI (21 mg, 0.128 mmol). The reaction mixture was stirred atroom temperature overnight. Solvent was removed and the residue wassubjected to prep-HPLC and prep-TLC purification to give the desiredproduct (2.8 mg, 53% yield). ¹H NMR (500 MHz, DMSO-d6) δ: 13.62 (s, 1H),10.56 (s, 1H), 8.75 (s, 1H), 8.594 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 7.78(d, J=5.0 Hz, 1H), 7.41 (s, 1H), 7.28-7.36 (m, 3H), 7.13 (s, 1H), 5.12(s, 2H), 2.59 (s, 3H). ESI-MS m/z: 417.1.

Example 14: Synthesis of6-(2-hydroxy-1-phenylethyl)-3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one6-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazol[4,3-g]quinolin-7-one

To a solution of3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one(14 mg, 0.025 mmol) in 3.0 mL of DMF at room temperature was added NBS(22 mg, 0.12 mmol). The reaction mixture was stirred at 50° C. for 1 h.The reaction mixture was diluted with ethyl acetate, washed with waterand dried over Na₂SO₄. The dried solution was concentrated and theresidue was subjected to a column purification to give the desiredproduct (12 mg, 75%).

3-(2-methylpyridin-4-yl)-6-(1-phenylvinyl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one

To a solution of6-bromo-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one(120 mg, 0.20 mmol) and (1-phenylvinyl)boronic acid (89 mg, 0.60 mmol)in 3.0 mL of 4:1 dioxane/water mixture at room temperature were addedPdCl₂(dppf) (33 mg, 0.04 mmol) and K₂CO₃ (83 mg, 0.60 mmol). Thereaction mixture was degassed and backfilled with nitrogen. The reactionmixture was stirred at 80° C. overnight. Solid was filtered off and thefiltrate was concentrated in vacuo. The residue was subjected to a flashcolumn chromatography purification to give the desired product (72 mg,58% yield).

6-(2-hydroxy-1-phenylethyl)-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one

A stirred solution of3-(2-methylpyridin-4-yl)-6-(1-phenylvinyl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one(96.8 mg, 0.16 mmol) in 5 mL anhydrous THF was cooled down to 0° C. inice-water bath, large excess of borane dimethyl sulfide complex (4 mL)was added dropwise. The reaction mixture was stirred at 0° C. for 2 hand then stirred at room temperature overnight. The reaction mixture wascooled to 0° C. and then 5 mL of deionized water was added. To thereaction mixture, was added 5 mL of 3 M NaOH, followed by 10 mL H₂O₂solution dropwise, and the resulting mixture was stirred at 50° C. for 1h. The reaction mixture was extracted 3 times with DCM. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated in vacuo toyield a brown solid as a crude product. The crude compound was used inthe next step without further purification.

6-(2-hydroxy-1-phenylethyl)-3-(2-methylpyridin-4-yl)-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-one

To a solution of the crude6-(2-hydroxy-1-phenylethyl)-3-(2-methylpyridin-4-yl)-1-trityl-1,8-dihydro-7H-pyrazolo[4,3-g]quinolin-7-onefrom the previous step in 10 mL of DCM, 1 mL of TFA was added and theresulting mixture was stirred at room temperature for 2 h. The mixturewas washed with saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄,and concentrated in vacuo. The residue was purified with columnchromatography on silica gel (10% MeOH in DCM,) to yield a yellow solidas the desired product (32 mg, 55% yield). ¹H NMR (500 MHz, DMSO-d6) δ:13.42 (s, 1H), 11.65 (s, 1H), 8.60 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.03(s, 1H), 7.93 (s, 1H), 7.86 (d, J=5.5 Hz, 1H), 7.37 (s, 1H), 7.33 (d,J=7.0 Hz, 2H), 7.29 (t, J=7.0 Hz, 2H), 7.19 (t, J=7.5 Hz, 1H), 4.84 (t,J=5.5 Hz, 1H), 4.34 (t, J=7.5 Hz, 1H), 4.00 (m, 1H), 3.90 (m, 1H), 2.60(s, 3H). ESI-MS m/z: 397.2.

Example 15: Synthesis of(6-benzyl-3-(2,6-dimethylpyridin-4-yl)-7-oxo-5,6,7,8-tetrahydro-1Hpyrazolo[4,3-g]quinazolin-1-yl)methyl(6-benzyl-3-(2,6-dimethylpyridin-4-yl)-7-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-1-yl)methylDi-tert-butyl Phosphate

To a stirred solution of6-benzyl-3-(2,6-dimethylpyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[4,3-g]quinazolin-7-one(76 mg, 0.20 mmol) in 5.0 mL of dry DMA at room temperature was addedCs₂CO₃ (196 mg, 0.60 mmol) followed by di-tert-butyl (chloromethyl)phosphate (78 mg, 0.30 mmol). The reaction mixture was stirred at the40° C. for 2 h. The reaction mixture was diluted with ethyl acetate andwashed with water. The organic solution was separated and dried. Thesolvent was removed and the residue was subjected a flash columnpurification to give the desired product (50 mg, 41% yield).

(6-benzyl-3-(2,6-dimethylpyridin-4-yl)-7-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-1-yl)methylDihydrogen Phosphate

A solution of(6-benzyl-3-(2,6-dimethylpyridin-4-yl)-7-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-g]quinazolin-1-yl)methyldi-tert-butyl phosphate (80 mg, 0.132 mmol) in 4.0 mL of 1:3 AcOH/H₂Owas stirred at 50° C. for 12 h. The reaction mixture was concentrated invacuo and the residue was subjected to a prep-HPLC purification to givethe desired product (38 mg, 58%). ¹H NMR (500 MHz, DMSO-d6) δ: 10.21 (s,1H), 8.23 (br, 1H), 7.90 (s, 1H), 7.60 (s, 2H), 7.28-7.41 (m, 5H), 5.91(s, 2H), 4.62 (s, 2H), 4.44 (s, 2H). ESI-MS m/z: 493.1.

Example 16: Synthesis of6-(3-chloro-4-fluorobenzyl)-3-(2-methylpyridin-4-yl)-1,8-dihydro-5H-pyrazolo[4,3-g]quinazoline-5,7(6H)-dione

To a stirred solution of6-(3-chloro-4-fluorobenzyl)-3-(2-methylpyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[4,3-g]quinazolin-7-one(8 mg, 0.02 mmol) in 2 mL of DMSO at room temperature was added KMnO₄(63 mg, 0.40 mmol). The reaction mixture was stirred at 60° C. for 2 h.Solid was filtered off and the resulting DMSO solution was subjected toprep-HPLC purification to give the desired product (2.5 mg 30%). ¹H NMR(500 MHz, DMSO-d6) δ: 13.71 (br, 1H), 11.60 (br, 1H), 8.74 (s, 1H), 8.59(d, J=5.0 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=5.5 Hz, 1H), 7.58 (dd,J=2.0, 7.0 Hz, 1H), 7.36-7.39 (m, 2H), 7.28 (s, 1H), 5.10 (s, 2H), 2.54(s, 3H). ESI-MS m/z: 435.1.

Example 17 Inhibition Assays of ERK

The inhibition of ERK activity by the compounds disclosed herein wasdetermined using the Z′-LYTE kinase assay kit (Life Technologies) with aSer/Thr 3 peptide substrate (Life Technologies) according tomanufacturers' instructions. The assay was run with an ERK2 enzyme (LifeTechnologies) concentration of 0.47 ng/μL at 100 μM ATP (approximatelythe ATP K_(m) for ERK2). The IC50 values for the compounds weredetermined with 3-fold serial dilutions in duplicate. The compounds werefirst diluted in 1:3 dilutions in 100% DMSO at 100× the desiredconcentration, and then further diluted (1:25) in 20 mM HEPES buffer(Invitrogen) to make 4× solutions prior to adding to the enzymesolution. The final DMSO concentration in the assay was 1%. Finalreaction volume was 20 μL/well in 384-well plates. Kinase reactions wereconducted or 1 hour followed by the assay development reaction (1 hour)in a 20 μl/well in a 384 well plate format. One or more compoundsdisclosed herein exhibited an IC50 less than 10 nM when tested in thisassay (see FIG. 1).

TABLE 1 In Vitro Erk2 IC50 data for selected compounds of the invention.Calculated Erk2 Molecular Mass Found No. Chemical Structure IC50 (nM)Weight (M + 1) 1

++++ 355.4 356.1 2

++++ 383.5 384.3 3

++++ 389.8 390.1 4

++++ 403.9 404.4 5

+++ 401.4 402.2 6

+++ 366.4 367.2 7

++++ 405.4 406.2 8

++++ 421.9 422.2 9

++++ 400.4 401.4 10

++++ 399.4 400.3 11

++++ 405.4 406.3 12

+++ 437.4 438.2 13

++++ 405.4 406.3 14

++++ 403.9 402.5 (M − 1) 15

+++ 435.8 436.1 16

++++ 417.9 418.2 17

+++ 413.4 414.2 18

++++ 401.4 402.2 19

++++ 355.4 356.2 20

+++ 369.4 370.2 21

+++ 384.4 385.2 22

++++ 380.4 381.2 23

++++ 408.5 409.2 24

+++ 417.1 418.1 25

++ 391.7 391 26

++++ 433.9 434.1 27

++++ 383.4 384.2 28

+++ 417.9 418.4 29

++ 374.0 375.2 30

++++ 387.4 388.2 31

++++ 410.8 411.1 32

+++ 362.4 363.2 33

++++ 376.5 377.3 34

+++ 362.4 363.2 35

++++ 417.9 418.1 36

++++ 437.9 438.1 37

++++ 438.8 439.1 38

++++ 437.9 438.1 39

++++ 394.4 395.2 40

+++ 424.8 425.1 41

++++ 437.9 438.2 42

+++ 370.8 371.1 43

++++ 323.3 325.2 44

++++ 363.4 364.2 45

++++ 381.4 382.2 46

+++ 350.4 351.2 47

++++ 376.4 377.1 48

++++ 396.8 397.1 49

++++ 363.4 364.2 50

++++ 417.9 418.1 51

++++ 392.5 393.2 52

++++ 337.4 338.2 53

++++ 363.5 364.2 54

++++ 337.4 338.2 55

++++ 394.4 395.2 56

++++ 376.4 377.2 57

++++ 389.8 390.1 58

++++ 403.9 404.1 59

++++ 429.9 430.1 60

++++ 378.8 379.1 61

++++ 405.8 406.1 62

+++ 416.5 417.3 63

++++ 452.6 453.3 64

++++ 394.5 395.3 65

++++ 408.5 409.2 66

++++ 390.8 391.1 67

++ 415.5 416.2 68

++++ 420.9 421.1 69

+++ 416.5 417.2 70

++++ 452.6 453.3 71

++++ 434.9 435.1 72

++++ 404.4 405.1 73

+ 412.5 413.2 74

+++ 433.9 434.1 75

++++ 419.9 420.1 76

++++ 403.4 404.1 77

++++ 417.9 418.1 78

++++ 397.9 398.1 79

++++ 417.4 418.2 80

++++ 418.4 419.1 81

++ 393.4 394.2 82

++ 447.5 448.3 83

++++ 322.4 323.2 84

++++ 380.4 381.2 85

++++ 433.9 434.1 86

++++ 434.9 435.1 87

++++ 421.4 422.1 88

++++ 422.4 423.1 89

++++ 466.9 467 90

++++ 404.9 405.1 91

+++ 389.8 390.1 92

++++ 421.4 422.1 93

++++ 405.8 406.1 94

+++ 413.9 414.1 95

++++ 434.9 435.1 96

+++ 310.3 311.1 97

++++ 374.4 375.1 98

+ 434.9 435.1 99

++++ 422.4 423.1 100

++++ 425.4 426.1 101

++++ 487.5 488.2 102

++++ 505.5 506.2 103

++++ 517.6 518.2 104

++++ 469.5 470.2 105

++++ 409.4 410.2 106

+++ 395.4 396.2 107

++ 448.9 449.1 108

+++ 403.9 404.1 109

+ 324.3 325.2 110

++++ 388.4 389.2 111

++++ 404.9 405.1 112

++++ 353.4 354.2 113

+++ 339.4 340.2 114

++++ 392.4 393.1 115

++++ 404.9 405.1 116

+++ 487.5 488.2 117

++++ 420.9 421.1 118

++++ 450.9 451.1 119

++++ 454.4 455.1 120

++++ 439.5 440.1 121

++++ 457.5 458.2 122

++++ 475.5 476.2 123

++++ 390.8 391.1 124

++++ 424.4 425.1 125

++++ 411.4 412.2 126

++++ 487.5 488.2 127

++++ 392.4 393.1 128

++++ 381.4 382.1 129

+++ 431.9 432.1 130

+++ 418.4 419.1 131

+++ 467.6 468.2 132

++++ 471.5 472.2 133

++++ 456.5 457.2 134

++++ 505.0 505.2 135

+++ 460.6 461.2 136

+++ 446.6 447.3 137

+++ 430.5 431.3 138

+++ 444.6 445.2 139

++++ 457.5 458.2 140

++++ 473.6 474.2 141

+++ 458.6 459.3 142

++++ 470.6 471.3 143

++++ 488.5 489.2 144

++++ 500.6 501.2 145

++++ 466.6 467.2 146

++++ 438.5 439.2 147

+++ 474.5 475.5 148

++++ 454.6 455.2 149

++++ 412.5 413.2 150

++++ 483.6 484.2 151

++++ 470.5 471.2 152

++++ 501.0 501.2 153

++++ 452.6 453.2 154

++++ 466.6 467.2 155

++++ 430.5 431.3 156

++++ 487.0 487.2 157

+++ 466.6 467.2 158

++++ 487.0 487.1 159

++++ 487.0 487.2 160

+++ 386.5 387.2 161

++++ 521.5 522.2 162

++++ 486.5 487.2 163

++++ 488.5 489.2 164

++++ 501.0 501.2 165

++++ 459.6 460.3 166

++++ 454.5 455.5 167

+++ 484.6 485.2 168

++++ 467.6 468.5 169

++++ 432.6 433.2 170

++++ 467.6 468.2 171

+++ 453.5 454.2 172

++++ 466.5 467.2 173

++++ 464.9 465.1 174

++++ 473.0 473.2 175

++++ 430.5 431.2 176

++++ 446.9 447.2 177

++++ 466.6 467.2 178

++++ 458.5 459.2 179

+++ 484.6 485.2 180

+++ 501.0 501.2 181

+++ 414.9 415.1 182

+++ 430.5 431.3 183

+++ 467.6 468.2 184

++++ 470.5 471.2 185

++++ 488.5 489.2 186

+++ 499.6 500.3 187

++++ 488.5 489.2 188

++++ 483.6 484.2 189

+++ 402.5 403.2 190

++++ 488.5 489.2 191

++++ 424.5 425.2 192

+++ 438.5 439.2 193

++++ 444.5 445.2 194

+++ 444.6 445.5 195

+++ 487.6 488.3 196

++++ 488.5 489.2 197

++++ 398.4 399.2 198

++ 388.5 389.1 199

++++ 457.5 458.2 200

++++ 488.5 489.4 201

++ 480.6 481.5 202

++ 524.5 525.2 203

++++ 460.6 461.5 204

++++ 361.4 362.3 205

++++ 347.4 348.3 206

++ 430.5 431.4 207

+++ 418.5 419.4 208

+++ 466.6 467.5 209

++++ 446.5 447.4 210

+++ 416.5 211

++++ 377.4 378.2 212

++++ 361.4 362.2 213

++++ 375.2 376.3 214

++++ 430.4 431.1 215

+++ 430.5 431.3 216

++++ 458.5 459.3 217

++++ 403.9 404.2 218

++++ 437.4 438.2 219

++++ 391.5 392.3 220

++++ 391.5 392.7 221

++++ 382.4 383.2 222

+++ 506.5 507.3 223

++++ 424.5 425.3 224

++++ 397.4 398.2 225

++++ 419.4 420.1 226

++++ 435.9 436.1 227

++++ 389.5 390.1 228

++++ 404.5 405.1 229

++++ 383.4 384.2 230

431.9 432.1 231

++++ 474.9 475.1 232

++++ 466.5 467.2 233

++++ 451.4 452.2 234

++++ 390.5 391.1 235

+++ 392.8 393.1 236

+++ 462.6 461.4 (M − 1) 237

++++ 444.5 445.2 238

+++ 453.5 454.2 239

++++ 361.4 362.2 240

++++ 437.4 438.2 241

++++ 438.5 439.2 242

+++ 520.5 521.3 243

++++ 333.4 334.2 244

++++ 458.5 459.3 245

++++ 472.6 473.2 246

++++ 390.5 391.1 247

++++ 404.5 405.3 248

++++ 452.6 453.3 249

+++ 458.9 459.2 250

++++ 391.5 392.2 251

++++ 472.6 472.3 (M − 1) 252

++++ 458.6 459.2 253

++++ 347.4 348.2 254

++++ 458.6 459.2 255

++++ 362.4 363.1 256

++++ 376.5 377.2 257

+++ 443.5 444.2 258

++++ 333.4 334.1 259

++++ 419.4 420.1 260

++ 486.0 486.2 261

++++ 441.5 442.2 262

++++ 391.5 392.2 263

++ 488.5 489.2 264

++++ 488.5 489.3 265

+++ 419.4 420.1 266

++++ 372.5 373.2 267

++++ 444.5 445.1 268

+++ 390.5 391.3 269

++++ 378.4 379.2 270

++++ 468.6 469.2 271

++++ 504.5 505.2 272

++++ 468.6 469.2 273

++++ 504.5 505.2 274

++++ 430.4 431.1 275

++++ 452.6 453.2 276

++++ 447.4 448.2 277

++++ 446.4 447.1 278

++++ 452.6 453.2 279

++++ 466.6 467.2 280

++++ 505.5 506.2 281

++++ 477.5 478.2 282

++++ 431.4 432.2 283

+++ 347.4 348.2 284

++++ 488.5 489.2 285

++++ 441.5 442.2 286

++++ 418.5 419.2 287

+++ 398.4 399.1 288

++++ 398.4 399.2 289

++++ 344.4 345.2 290

++++ 476.6 477.2 291

++++ 476.6 477.3 292

++++ 453.5 454.3 293

++++ 489.5 490.3 294

++++ 375.5 376.2 295

++++ 475.6 476.2 296

+++ 466.6 467.3 297

++++ 466.6 467.2 298

++++ 447.6 448.2 299

++++ 430.4 431.2 300

++++ 524.5 525.2 301

++++ 438.5 439.2 302

++++ 444.5 445.2 303

++ 506.5 507.2 304

++++ 506.5 507.2 305

+++ 470.5 471.2 306

++++ 470.5 471.2 307

+++ 452.6 453.2 308

++++ 452.6 453.2 309

+++ 444.5 445.2 310

++++ 444.5 445.2 311

+++ 524.5 525.2 312

+++ 416.4 417.2 313

++++ 466.6 467.3 314 ++++ 373.5 374.2 315 ++++ 447.5 370.1 316 ++++464.6 465.3 317 +++ 369.4 370.2 318

++++ 464.6 465.3 319

+++ 470.5 471.2 320

+++ 505.5 506.3 321

++++ 512.6 513.3 322

+++ 472.5 473.3 323

++++ 367.4 368.2 324

+++ 451.5 452.3 325

++++ 451.5 452.3 326

++++ 366.4 367.2 327

++ 404.5 405.3 328

++++ 396.4 397.2 329

++ 486.5 487.4 330

++++ 366.4 367.2 331

++++ 498.4 499.3 332

++++ 449.5 450.4 333

++++ 369.4 370.2 334

++++ 382.4 383.2 335

++++ 380.4 381.2 336

++++ 485.5 486.2 338

++++ 388.5 389.2 339

++++ 520.5 521.4 340

++++ 493.5 494.4 341

++++ 492.5 493.3 342

++++ 492.5 493.3 343

+++ 380.4 381.2 344

++++ 381.4 382.1 345

++++ 374.4 375.2 346

++++ 522.5 523.3 347

++++ 396.4 397.1 348

++++ 523.5 524.4 349

++++ 507.5 508.3 350

++ 495.5 496.3 351

++++ 508.5 509.2 352

++++ 495.5 496.2 353

++++ 454.5 455.3 354

++++ 454.5 455.3 355

++++ 455.5 456.3 356

++++ 477.6 478.3 357

++++ 388.5 389.2 358

+++ 387.5 388.2 359

+++ 508.6 509.3 360

+++ 463.6 464.3 361

+++ 514.5 515.3 362

++++ 488.5 489.2 363

++++ 466.6 467.3 364

++++ 466.5 467.3 365

+++ 469.5 470.3 366

++++ 463.5 464.2 367

+++ 465.5 466.3 368

+++ 468.6 469.3 369

++ 504.5 505.4 370

++++ 465.5 466.4 371

+++ 382.5 383.2 372

++++ 369.4 370.2 373

+++ 449.5 450.3 374

++++ 522.5 523.3 375

+++ 522.5 523.3 376

++++ 468.6 469.3 377

++++ 397.5 398.3 378

+++ 455.2 456.2 379

++++ 502.2 503.2 380 466.3 467.3 381 450.2 451.3 382

429.3 430.2 383

488.2 489.3 384

488.2 489.3 385

502.2 503.3 386

502.2 503.3 387

520.2 521.2 388

464.6 465.3 389

478.6 479.3 The following symbols are used: + (greater than 1000 nM), ++(250 nM to 1000 nM), +++ (50 nM to 250 nM), and ++++ (less than 50 nM).

Example 18. Phospho-p90 RSK ELISA Using A375 (Braf V600E) Cells

On day 1, A375 cells (melanoma cell line with a Braf V600E mutation)were grown to near 80% confluence, trypsinized, and seeded at 50,000cells per well in a 100 μL of full growth medium (10% FBS in DMEM) in a96-well plate. Cells were incubated at 37° C. under 5% CO₂ overnightprior to treatment. In preparation for the assay, an ELISA plate withthe pre-coated goat anti-mouse antibody (Thermo Scientific) was treatedwith a mouse anti-human RSK1 antibody (monoclonal, Invitrogen) at 1:800dilution (150 ng/well) in PBS, and the plate was placed on a plateshaker at 4° C. overnight. On day 3, the compounds were first diluted in1:3 dilutions in 100% DMSO at 250× the desired concentration, and thenfurther diluted (1:50) in 10% DMEM growth medium. The diluted compoundsare added to the cell plate (25 μL for a 5× dilution) and the cells weretreated with compounds (0.4% DMSO in 10% FBS DMEM) for 2 hours at 37° C.under 5% CO2. The cell control wells were added with vehicle only (0.4%DMSO in 10% FBS DMEM). Each concentration of the compounds was tested induplicate. After two hours of the compound treatment, the supernatantwas removed from the cell plate, and cells were lysed in 100 μl per wellof cell lysis buffer (Cell Signaling Technologies) containingphosphatase and protease inhibitors (Cell Signaling Technologies) on aplate shaker at 4° C. for 20 minutes. The ELISA plate was washed fourtimes with ELISA wash buffer (Thermo Scientific) prior to addition of100 μL cell lysate. The lysate was incubated on the ELISA plate withgentle shaking at room temperature for 2 hours. The contents of thewells were removed, and the ELISA plate was washed four times with washbuffer, and incubated with 100 μL per well of anti-phospho-RSK1(Thr359/Ser363) rabbit monoclonal antibody (Millipore) at dilution of1:1000 in StartingBlock buffer (Thermo Scientific) on a plate shaker atroom temperature for 1 hour. The contents of the wells were removed, theELISA plate was washed four times with wash buffer, and was incubatedwith 100 μL per well of goat anti-rabbit HRP (Thermo Scientific) atdilution of 1:3000 in StartingBlock buffer (Thermo Scientific) on aplate shaker at room temperature for 1 hour. The contents of the wellswere removed, the ELISA plate was washed four times with wash buffer,and then incubated with 100 μL per well of TMB substrate solution(Thermo Scientific) on a plate shaker at room temperature for 20minutes. Finally, 100 μL of TMB stop solution (Thermo Scientific) wasadded to each well and the absorbance is measured at 450 nm on a Tecanplate reader. One or more compounds disclosed herein exhibit an EC50less than 50 nM when tested in this assay (see FIG. 1).

Example 19. Tumor Cell Line Proliferation Assay

The ability of one or more compounds of the invention to inhibit tumorcell line proliferation was determined according to standard proceduresknown in the art. For instance, an in vitro cellular proliferation assaywas performed to measure the metabolic activity of live cells. Tumorcell lines A375, WM-266-4, or HCT116 cells (ATCC) were grown to near 80%confluence, and are trypsinized and seeded at 1500 cells/well at volumeof 100 per well in full growth medium (10% FBS in DMEM or 10% FBS inRPMI) in a 96 well plate. The cells were incubated at 37° C. under 5%CO₂for two hours to allow for attachment to the plates. Compounds werefirst diluted in 1:3 dilutions in 100% DMSO at 250× the desiredconcentration, and then further diluted (1:50) in 10% DMEM growthmedium. The diluted compounds were added to the cell plate (25 μL for a5× dilution) and the cells are incubated with compounds (0.4% DMSO in10% FBS DMEM) for 96 hours at 37° C. under 5% CO2. The cell controlwells were added with vehicle only (0.4% DMSO in 10% FBS DMEM or in 10%FBS RPMI). Each concentration of the compounds was tested in duplicates.After 96 hours of the compound treatment, CellTiter Glo reagent(Promega) was added at a 1:5 dilution to each well of the cell plate andthe cell plate was placed at room temperature for 30 minutes. Theluminescence of the wells was determined using a Tecan plate reader. Oneor more compounds disclosed herein exhibit an IC50 less than 80 nM inA375 cells, an IC50 less than 50 nM in HCT1116 cells, and an IC50 lessthan 110 nM in H358 cells when tested in this assay (see FIG. 1).

TABLE 2 In Vitro IC50 data for selected compounds of the invention (thecompounds numbers correspond to those provided in Table 1). 250 nM orless 250 nM to Greater than (+++) 1000 nM (++) 1000 nM (+) Cellular 1,2, 3, 4, 6, 5, 915, 17, 19, 20, 32, 33, 34, Phospho- 7, 8, 10, 11, 21,27, 36, 38, 40, 42, 43, 46, p90RSK 12, 13, 14, 16, 39, 44, 45, 47, 51,54, 59, 60, IC50 (nM) 18, 22, 23, 26, 48, 49, 53, 56, 61, 67, 83, 30,31, 35, 37, 62, 66, 70, 95, 117, 128, 131, 41, 50, 55, 57, 97, 100, 110,133, 151, 157, 58, 63, 64, 68, 111, 114, 115, 160, 164, 166, 71, 72, 75,76, 124, 125, 127, 167, 171, 173, 77, 78, 84, 86, 129, 136, 137, 189,201, 202, 88, 90, 92, 99, 138, 139, 145, 206, 208, 210, 101, 102, 103,149, 152, 155, 235, 236, 247, 104, 118, 120, 159, 168, 169, 255, 256,260, 121, 122, 123, 170, 172, 175, 263, 265, 268, 126, 132, 134, 176,177, 182, 283, 296, 303, 140, 141, 142, 183, 186, 191, 314, 317, 327,143, 144, 146, 192, 194, 195, 329, 335,, 147, 148, 150, 203, 204, 207,343, 350, 358, 153, 154, 156, 209, 215, 218, 363, 365, 383, 158, 161,162, 219, 221, 223, 385 163, 165, 174, 230, 232,, 178, 179, 180, 257,287, 289, 181, 184, 185, 307, 309, 310, 187, 188, 190, 313, 315, 319,193, 196, 197, 322, 331, 351, 199, 200, 205, 355, 359, 360, 211, 212,213, 367, 371, 373, 214, 216, 217, 387 220, 222, 224, 225, 226, 227,228, 229, 231, 233, 234, 237, 238, 239, 240, 241, 242, 243, 244, 245,246, 248, 249, 250, 251, 252, 253, 254, 258, 259, 261, 262, 264, 266,267, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281,284, 285, 286, 288, 290, 291, 292, 293, 294, 295, 297, 298, 299, 300,301, 302, 304, 305, 306, 308, 311, 312, 316, 318, 320, 321, 323, 324,325, 326, 328, 330, 332, 333, 334, 336, 338, 339, 340, 341, 342, 344,345, 346, 347, 348, 349, 352, 353, 354, 356, 357, 361, 362, 364, 366,370, 372, 380, 384, 386 A375 (V599E) 1, 3, 4, 22, 2, 6, 7, 8, 10, 5, 9,15, 17, Cell 63, 64, 68, 11, 12, 13, 14, 19, 20, 24, 27, Proliferation77, 84, 101, 16, 18, 21, 23, 32, 33, 34, 39, IC50 (nM) 102, 103, 104,26, 30, 31, 35, 47, 49, 201, 134, 143, 144, 36, 37, 41, 92, 202, 257,317, 146, 148, 149, 99, 120, 123, 366 151, 153, 154, 132, 136, 138, 156,158, 162, 139, 140, 141, 165, 181, 184, 147, 161, 163, 185, 187, 190,174, 178, 179, 196, 197, 212, 180, 193, 199, 213, 214, 225, 200, 204,205, 237, 239, 240, 211, 216, 221, 241, 243, 244, 222, 224, 226, 245,248, 251, 227, 228, 229, 252, 254, 264, 231, 234, 242, 267, 269, 270,301, 308, 311, 271, 272, 273, 320, 321, 323, 275, 278, 279, 328, 330,331, 280, 281, 284, 285, 288, 291, 292, 293, 304, 305, 306, 316, 318,324, 325, 326, 332, 333, 338, 339, 357, 362, 364 H358 1, 35, 63, 64, 30,31, 36, 37, 26, 27, 32, 33, (Kras, G12C) 84, 101, 102, 39, 41, 68, 77,34, 47, 49, Cell 103, 143, 144, 99, 120, 123, 136, 138, 201,Proliferation 146, 147, 165, 132, 134, 139, 202, 204 IC50 (nM) 174, 181,196, 140, 141, 161, 197, 214 163, 178, 179, 180, 190, 193, 199, 200,205, 221, 222 WM-266-4 1, 3, 4, 7, 8, 2, 5, 6, 9, 13, 15, 17, 19, 20,(V599D) 10, 11, 12, 22 14, 16, 18, 21 23, 24 Cell Proliferation IC50(nM)

Example 20. Microsome Stability Assay

The stability of one or more compounds of the invention is determinedaccording to standard procedures known in the art. For example,stability of one or more compounds of the invention is established by anin vitro assay. In particular, an in vitro microsome stability assay isestablished that measures stability of one or more compounds of theinvention when reacting with mouse, rat or human microsomes from liver.The microsome reaction with compounds is performed in 1.5 mL Eppendorftube. Each tube contains 0.1 μL of 10.0 mg/ml NADPH; 75 μL of 20.0 mg/mlmouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer,and 425 μL of ddH₂O. Negative control (without NADPH) tube contains 75μL of 20.0 mg/ml mouse, rat or human liver microsome; 0.4 μL of 0.2 Mphosphate buffer, and 525 μL of ddH₂O. The reaction is started by adding1.0 μL of 10.0 mM tested compound. The reaction tubes are incubated at370° C. 100 μL sample is collected into new Eppendorf tube containing300 μL cold Methanol at 0, 5, 10, 15, 30 and 60 minutes of reaction.Samples are centrifuged at 15,000 rpm to remove protein. Supernatant ofcentrifuged sample is transferred to new tube. Concentration of stablecompound after reaction with microsome in the supernatant is measured byLiquid Chromatography/Mass Spectrometry (LC-MS). The microsome stabilityof one or more compounds of the present invention when assayed underthis condition have T1/2 (min) well within a range required for clinicaldevelopment.

Example 21. Plasma Stability Assay

The stability of one or more compounds of the invention in plasma isdetermined according to standard procedures known in the art. See, e.g.,Rapid Commun. Mass Spectrom., 10: 1019-1026. The following procedure isan HPLC-MS/MS assay using human plasma; other species including monkey,dog, rat, and mouse are also available. Frozen, heparinized human plasmais thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4°C. prior to use. A compound of the invention is added from a 400 μMstock solution to an aliquot of pre-warmed plasma to give a final assayvolume of 400 μL (or 800 μL for half-life determination), containing 5μM test compound and 0.5% DMSO. Reactions are incubated, with shaking,for 0 minutes and 60 minutes at 37° C., or for 0, 15, 30, 45 and 60minutes at 37° C. for half life determination. Reactions are stopped bytransferring 50 μL of the incubation mixture to 200 μL of ice-coldacetonitrile and mixed by shaking for 5 minutes. The samples arecentrifuged at 6000×g for 15 minutes at 4° C. and 120 μL of supernatantremoved into clean tubes. The samples are then evaporated to dryness andsubmitted for analysis by HPLC-MS/MS.

Where desired, one or more control or reference compounds (5 μM) aretested simultaneously with the test compounds: one compound,propoxycaine, with low plasma stability and another compound,propantheline, with intermediate plasma stability.

Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v)and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 60 minutes relative to the amountremaining at time zero, expressed as percent, is reported as plasmastability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 22. Chemical Stability Assay

The chemical stability of one or more compounds of the invention isdetermined according to standard procedures known in the art. Thefollowing details an exemplary procedure for ascertaining chemicalstability of a subject compound. The default buffer used for thechemical stability assay is phosphate-buffered saline (PBS) at pH 7.4;other suitable buffers can be used. A compound of the invention is addedfrom a 100 μM stock solution to an aliquot of PBS (in duplicate) to givea final assay volume of 400 μL, containing 5 μM test compound and 1%DMSO (for half-life determination a total sample volume of 700 μL isprepared). Reactions are incubated, with shaking, for 0 minutes and 24hours at 37° C.; for half-life determination samples are incubated for0, 2, 4, 6, and 24 hours. Reactions are stopped by adding immediately100 μL of the incubation mixture to 100 μL of acetonitrile and vortexingfor 5 minutes. The samples are then stored at −20° C. until analysis byHPLC-MS/MS. Where desired, a control compound or a reference compoundsuch as chlorambucil (5 μM) is tested simultaneously with a compound ofthe invention of interest, as this compound is largely hydrolyzed overthe course of 24 hours. Samples are analyzed via (RP)HPLC-MS/MS usingselected reaction monitoring (SRM). The HPLC conditions consist of abinary LC pump with autosampler, a mixed-mode, C12, 2×20 mm column, anda gradient program. Peak areas corresponding to the analytes arerecorded by HPLC-MS/MS. The ratio of the parent compound remaining after24 hours relative to the amount remaining at time zero, expressed aspercent, is reported as chemical stability. In case of half-lifedetermination, the half-life is estimated from the slope of the initiallinear range of the logarithmic curve of compound remaining (%) vs.time, assuming first order kinetics.

Example 23. Rodent Pharmacokinetic Assay

In order to study the pharmacokinetics of the compounds of theinvention, the compounds are dissolved in an appropriate vehicle (e.g.5% 1-methyl-2-pyrrolidinone, 85% polyethylene glycol 400, 10% Solutor)and administered orally to a group of 4-10 week old mice at 12 hourintervals daily. All animals are euthanized in CO₂ hours after the finalcompound is administered. Blood is collected immediately and kept on icefor plasma isolation. Plasma is isolated by centrifuging at 5000 rpm for10 minutes. Harvested plasma is frozen for pharmacokinetic detection.

Alternatively, the compounds are dosed acutely (e.g. once) and after atime (e.g. about 0, 30 s, 1 m, 5 m, 10 m, 20 m, 30 in, 1 hr, 2 hr, 3 hr,5 hr, 8 hr, 10 hr, 12 hr, 1 d, 2 d, etc.) blood is collected andanalyzed as described below.

The results are expected to demonstrate the pharmacokinetic parameterssuch as absorption, distribution, metabolism, excretion, and toxicityfor the compounds of the invention.

Example 24. Inhibition of Tumor Growth In Vivo

Cell lines: Human cancer cell lines with A375 (mutant B-Raf V600E), LOX(mutant B-Raf V600E) and Colo-205 (mutant B-Raf V600E), PANC-1 (mutantK-Ras G12D), MiaPaca-2 (mutant K-Ras G12C), HCT116 (mutant K-Ras G13D),H441 (mutant K-Ras G12V), H23 (mutant K-Ras G12C), MDA-MB-231 (mutantK-Ras G13D) and LS1034 (mutant N-Ras) are obtained from ATCC. The cellsare maintained in cell culture in media recommended by ATCC at 37° C. in5% CO₂/air. The cells are harvested during exponential growth phase

Animals: 5-7 week-old female balb/c nude, CB17.SCID (severe combinedimmune deficiency) or SCID/beige mice are obtained from Charles RiverLaboratories. Animals are housed in disposable and individuallyventilated cages placed in SPF rooms or barrier rooms underpathogen-free conditions. Animals are fed with sterilized standard drygranule mouse chow and have free access to sterile water. All studiesare approved by the Institutional Animal Care and Use Committee ofExplora Biolabs where the studies are performed, and are in accordancewith Institutional Animal Care and Use Committee guidelines ofWellspring Biosciences and in accordance with the Guide for the Care andUse of Laboratory Animals (1996).

Tumor Xenograft Model: The mice are inoculated subcutaneously (2˜5×10⁶cells in PBS or PBS:Matrigel mixture) into the right flank of 7-9 weekold mice. Animal body weights are measured 3 times/week until treatmentbegins at which time body weights are measured daily prior to dosing.Tumor dimensions are measured 2˜3 times/week using a caliper. Tumorvolume is calculated using Formula I of (L×W²)/2, where L is tumorlength and W is tumor width, respectively. Typically dosing will beginwhen an average size of 100 mm³ is reached. Mice are randomized intostudy groups (n=9˜10/group). Compounds are formulated in PBS, PEG300(Polyethylene Glycol) or CMC/H₂O (Carboxymethyl Cellulose) andadministered to animals according to body weight (5 μL/mg) orally, QD orBID. Animals are sacrificed once tumors in the vehicle control groupreach 2000 mm³ in volume. For luciferase-transfected tumor models, tumorviability is monitored 2-3 times/week using the Xenogen IVIS® 200.

Data and Statistical Analysis: Tumor growth inhibition (TGI) iscalculated as [1−(T−T₀)/(C−C₀)]/100, where T and T₀ are the mean tumorvolumes for a treatment group on a specific experimental day and on thefirst day of treatment, respectively, for the experimental groups; C andC₀ are the mean tumor volumes for the control group.

The data is expressed as mean±SEM (standard error of the mean). Thestatistical significance in mean values is determined by ANOVA (analysisof variance) using a Dunnett's multiple-comparison post-test (GraphPadPrism®), or Tukey's test (SPSS 16.0). A P-value <0.05 is consideredstatistically significant.

1-64. (canceled)
 65. A method of treating cancer in a subject in needthereof, comprising administering to the subject an effective amount ofa compound of Formula II-E and an anti-cancer agent; wherein thecompound of Formula II-E has the structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: R₁ is3- to 6-membered heterocyclyl, —C₁₋₁₀alkyl-(3- to 6-memberedheterocyclyl), -(3- to 6-membered heterocyclyl)-C₁₋₁₀alkyl, -(3- to6-membered heterocyclyl)-C₃₋₁₀aryl, or -(3- to 6-memberedheterocyclyl)-C₁₋₁₀hetaryl, each of which is unsubstituted orsubstituted by one or more independent R₁₀ or R₁₁substituents; R₂₁ ishalogen, -L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl,-L-C₃₋₁₀cycloalkyl, -L-C₁₋₁₀heterocyclyl, -L-C₁₋₁₀alkyl-C₃₋₁₀aryl,-L-C₁₋₁₀alkyl-C₁₋₁₀hetaryl, -L-C₁₋₁₀alkyl-C₃₋₁₀cycloalkyl,-L-C₁₋₁₀alkyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkenyl-C₃₋₁₀aryl,-L-C₂₋₁₀alkenyl-C₁₋₁₀hetaryl, -L-C₂₋₁₀alkenyl-C₃₋₁₀cycloalkyl,-L-C₂₋₁₀alkenyl-C₁₋₁₀heterocyclyl, -L-C₂₋₁₀alkynyl-C₃₋₁₀aryl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀aryl, -L-C₁₋₁₀heteroalkyl-C₁₋₁₀hetaryl,-L-C₁₋₁₀heteroalkyl-C₃₋₁₀cycloalkyl, or-L-C₁₋₁₀heteroalkyl-C₁₋₁₀heterocyclyl, each of which is substituted byone or more independent R₁₂ substituents; L is a bond, —O—, —N(R³¹)—,—S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R³¹)—, —N(R³¹)C(═O)—,—NR³¹C(═O)O—, —NR³¹C(═O)NR³²—, —NR³¹S(O)₀₋₂—, —S(O)₀₋₂N(R³¹)—, —C(═S)O—,—C(═O)S—, —NR³¹C(═NR³²)NR³²—, —NR³¹C(═NR³²)O—, —NR³¹C(═NR³²)S—,—OC(═O)O—, —OC(═O)NR³¹—, —OC(═O)S—, —SC(═O)S—, —P(O)OR³¹—, or—SC(═O)NR³¹—; R₇₂ is hydrogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —C(O)R³¹, —CO₂R³¹,—C(═O)NR³¹, —S(O)₀₋₂R³¹, —C(═S)OR³¹, or —C(═O)SR³¹; R₁₀ is —C₁₋₁₀alkyl,—C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl,—C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, each of which isoptionally substituted by one or more independent R₁₁ substituents; R₁₁and R₁₂ are independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, —C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, —OR³¹, —NR³¹R³²,—C(O)R³¹, —CO₂R³¹, —C(═O)NR³¹, —NO₂, —CN, —S(O)₀₋₂R³¹, —SO₂NR³¹R³²,—NR³¹C(═O)R³², -NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³²R³³, —NR³¹C(═NR³²)R³³,—NR³¹C(═NR³²)SR³³, —OC(═O)OR³³, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)SR³¹, —P(O)OR³¹OR³², or —SC(═O)NR³¹NR³²; and each of R³¹, R³²,and R³³ is independently hydrogen, halogen, —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl,—C₂₋₁₀alkynyl, —C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl, or —R³¹ together with R³² forma heterocyclic ring.
 66. The method of claim 65, wherein R₂₁ is halogen,-L-C₁₋₁₀heteroalkyl, -L-C₃₋₁₀aryl, -L-C₁₋₁₀hetaryl, -L-C₃₋₁₀cycloalkyl,or -L-C₁₋₁₀heterocyclyl, each of which is substituted by one or moreindependent R₁₂ substituents.
 67. The method of claim 65, wherein L is abond, —O—, —N(R³¹)—, —S(O)₀₋₂—, —C(═O)—, —C(═O)O—, —OC(═O)—,—C(═O)N(R³¹)—, or —N(R³¹)C(═O)—.
 68. The method of claim 65, wherein Lis a bond.
 69. The method of claim 65, wherein R₂₁ is -L-C₁₋₁₀hetarylsubstituted by one or more independent R₁₂ substituents; and wherein Lis a bond.
 70. The method of claim 69, wherein the C₁₋₁₀hetaryl of R₂₁is selected from the group consisting of pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, and pyridazinyl.
 71. The method of claim 69,wherein each R₁₂ substituent is independently selected from the groupconsisting of —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₂₋₁₀alkynyl,—C₁₋₁₀heteroalkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl, —C₃₋₁₀cycloalkyl,—C₁₋₁₀heterocyclyl, —OH, —CF₃, —OCF₃, and —OR³¹; wherein each R³¹ isindependently hydrogen or —C₁₋₁₀ alkyl.
 72. The method of claim 71,wherein each R₁₂ substituent is independently selected from the groupconsisting -Me, -Et, -i-Pr, -n-Pr, OH, -OMe, -OEt, and -OPr.
 73. Themethod of claim 65, wherein R₁ is 3- to 6-membered heterocyclyl,unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.
 74. The method of claim 65, wherein R₁ is -(3- to6-membered heterocyclyl)-C₁₋₁₀alkyl, unsubstituted or substituted by oneor more independent R₁₀ or R₁₁ substituents.
 75. The method of claim 65,wherein R₁ is -(3- to 6-membered heterocyclyl)-C₃₋₁₀aryl, unsubstitutedor substituted by one or more independent R₁₀ or R₁₁ substituents. 76.The method of claim 65, wherein R₁ is

unsubstituted or substituted by one or more independent R₁₀ or R₁₁substituents.
 77. The method of claim 65, wherein R₁ is substituted withone or more R₁₀ substituents.
 78. The method of claim 77, wherein eachR₁₀ is independently —C₁₋₁₀ alkyl, —C₃₋₁₀aryl, —C₁₋₁₀hetaryl,—C₃₋₁₀cycloalkyl, or —C₁₋₁₀heterocyclyl.
 79. The method of claim 65,wherein R₇₂ is H.
 80. The method of claim 65, wherein the cancer isselected from the group consisting of breast cancer, pancreatic cancer,non-small cell lung cancer, thyroid cancer, seminomas, melanoma, bladdercancer, liver cancer, kidney cancer, myelodysplastic syndrome, acutemyelogenous leukemia, and colorectal cancer.
 81. The method of claim 80,wherein the cancer is melanoma or colorectal cancer.
 82. The method ofclaim 65, wherein the anti-cancer agent is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.83. The method of claim 65, further comprising radiation therapy.